Dry powder compositions for intranasal delivery

ABSTRACT

A pharmaceutical composition in a form of dry powder for intranasal administration includes solid particles of at least one opioid receptor antagonist as active ingredient and two types of solid particles. A naloxone pharmaceutical composition in the form of dry powder for intranasal administration, including as active agent naloxone or a pharmaceutically acceptable salt thereof. A kit for intranasal administration of naloxone. A method of treating opioid overdose/intoxication and/or a symptom thereof in a patient in need thereof by intranasally administering a therapeutically effective amount of a composition including solid particles of at least one opioid receptor antagonist as active ingredient and two types of solid particles.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/952,278 filed on Nov. 19, 2020, which is acontinuation-in-part of U.S. patent application Ser. No. 16/636,178filed on Aug. 19, 2019 (ex PCT Application PCT/IL2018/050914), claimingpriority form U.S. Application Ser. No. 62/547,858 filed on Aug. 20,2017, all fully incorporated herein by reference.

TECHNICAL FIELD

The present application relates to delivery of drugs in powder form byintranasal administration of a pharmaceutical composition comprising atleast one active agent, particularly an opioid receptor antagonist, andlactose or a lactose functional analogue as dry powder particles ofspecific particle size. The present application further relates tomethods for the preparation of the said pharmaceutical compositions and,more particularly, to methods of treatment of a subject in need thereofby administration of at least one pharmaceutical active agent viaintranasal delivery to the uppermost region of the nasal cavity.

BACKGROUND

Several publications are referred to herein, indicated by Arab numeralsin parenthesis. A full list of these reference appears at the end of thedescription immediately preceding the claims. These publications as wellas all other publications mentioned herein are fully incorporated hereinby reference.

Intranasal delivery has a number of compelling advantages over otherroutes of administration, namely its non-invasiveness, rapid attainmentof therapeutically relevant concentrations to the bloodstream, nofirst-pass metabolism, and ease of administration. Viable nasal deliverytechnologies have the potential to enable drug developers in creatinginnovative medicines using already approved products by delivering themthrough new routes of administration.

The intranasal delivery of drugs utilizes devices of several types, suchas nebulizers, pressurized devices, dry powder sprayers, andbi-directional nasal devices. Dry powders are used in intranasal drugdelivery due to many advantages of using this dosage form including theimproved stability, administration of larger doses and lack of microbialgrowth (no need for preservatives). The administration of intranasalpowders may improve patient compliance, especially if the smell andtaste of the delivered composition comprising excipients is unpleasant.Compared to drug solutions, the administration of powders covering ofthe upper and back parts of the nasal cavity and being a prolongedcontact with the nasal mucosa can result in improved delivery of thedrug. Powder form is suitable for delivery of both small molecules andbiologics, especially peptides, hormones and antibodies.

Traditionally, intranasal preparations have been used for localadministration of anti-histamines, decongestants and steroids, foralleviation of cold, allergy symptoms and/or nasal congestion. Morerecently, researchers' attention has been focused on two specific areas:

-   (1) The potential rapid drug absorption into the systemic    circulation provided by turbinate and lymphoid tissues located at    the back of the nasal cavity. This has already been in use in a    number of indications e.g. migraine and pain relief, osteoporosis,    vaccines, etc., and-   (2) The potential of the “Nose to Brain” (N2B) delivery to the    central nervous system (CNS) presented by the olfactory region at    the top of the nasal cavity, for the treatment of central nervous    system (CNS) diseases. Blood brain barrier (BBB) prevents the    treatment of neurological diseases by many potential drugs. Among    them are Alzheimer's, Parkinson's, stroke, spinal cord injury,    depression, and other CNS disorders. The blood-brain barrier is    related primarily to the endothelium of the brain capillaries,    through which few molecules can pass.

There are many advantages to the intranasal administration ofmedications that include, among others, a direct route to the bloodstream, avoidance of hepatic first pass metabolism, higherbioavailability, ease and convenience of non-invasive manipulation, andproximity to the central nervous system. In addition, direct delivery ofdrugs to the brain provides the possibility of a bettertherapeutic-toxic ratio than with systemic drug delivery.

The olfactory region inside the nasal cavity, involved in sensing odorsand chemicals, provides a unique and direct connection between the brainand the external environment. A number of studies reported drugs that donot or poorly cross the blood-brain barrier, but are rapidly deliveredto the CNS when delivered intranasally, preferably delivered directly tothe turbinate and lymphoid tissues located at the back of the nasalcavity. A free communication exists between the nasal submucosalinterstitial space and the olfactory perineuronal space, which iscontiguous with a subarachnoid extension that surroundings the olfactorynerve. The olfactory epithelium is capable of metabolizing some drugs.The olfactory neuronal pathway includes both the intracellular(intraneuronal) and extracellular (extraneuronal) pathway into thebrain. After reaching the olfactory bulb and/or trigeminal region theactive ingredient/s may penetrate other brain regions by diffusion,which may also be facilitated by arterial pulsation. In addition,intranasally administered drugs may also partially enter into CNS afterits penetration into the systemic blood circulation.

Mostly hydrophilic drugs like dopamine and picolinic acid can betransported through the olfactory pathway. In case of lipophilic drugs,the systemic route is better than olfactory route because it can crossthe blood brain barrier (BBB). Singh et al showed that alprazolam loadedin solid-lipid nanoparticles was rapidly transferred to the rabbit brainvia intranasal route, bypassing the blood-brain barrier (1). Theenhanced rate and extent of transport may help in reducing the dose anddosing frequency, thereby providing a better compliance for ambulatorypatients. Another study confirmed that intranasal oxytocinadministration could increase confidence in human subjects (2).

Moreover, an increasing number of studies on both animals and humansubjects suggested that intranasal drug delivery could be used totransfer not only small molecules but also large sized biologics intothe CNS by bypassing the BBB. Benedict et al showed that insulinadministration by the intranasal route may improve memory and mood ofhealthy adults (3). Freiherr et al (4) and Reger et al (5) demonstratedthat the memory of AD patients may also be approved without alteringblood levels of insulin or glucose. Jin et al reported that intranasaladministration of either fibroblast growth factor-2 or heparin-bindingepidermal growth factor may have potential as neurogenesis-promotingtherapeutic agents (6). All aforementioned pharmaceutical activeingredients were administered to the nasal cavity as sprays.

While intranasal delivery specifically to the olfactory regionpotentially provides a route for delivery of agents to the CNS, theolfactory region is difficult to access using conventional nasaldelivery devices. The olfactory region is located in the uppermostregion of the nasal cavity, where less than 10% of the inhaled airflows. Conventional nasal sprays deposit the majority of the drug in thelower region of the nasal cavity, with very little drug reaching theolfactory region. Improved devices for the spray delivery to theolfactory region are described in U.S. Patent Application No.20070119451. The devices include a nosepiece and an elongated tubularmember slidably disposed within the nosepiece for movement between aretracted position and an extended position. The tubular member is inflow communication with a reservoir containing the substance to bedelivered. During the use, the tubular member extends from the device,to direct the substance toward the olfactory region. However, thisreference does not disclose delivery of solid dry powders. Similardevices are disclosed in U.S. 20030178440, U.S. Pat. Nos. 6,866,039,6,945,953 and U.S. 20050028813.

U.S. Pat. No. 9,556,260 described methods and compositions for thetreatment of CNS disorders via intranasal administration of pooled humanimmunoglobulin G. As shown therein, intranasal administration allows thedirected delivery of intact IgG to the brain bypassing the need to passthrough the BBB. This results in greater efficiency for the treatmentand reduces the necessary IgG dose that must be administered to achievethe desired effect. Whilst pooled human IgG is isolated from donatedhuman plasma, pooled IgG is a limited resource. Therefore, if madepossible, the reduction in the effective dose of IgG would effectivelyincrease the therapeutic potential. Furthermore, intranasaladministration of IgG nearly eliminates the systemic exposure caused byintravenous administration, improving the overall safety profile of thetreatment. Also, it would be beneficial to intranasally administer IgGto the brain in the absence of permeability enhancers, some of which hasneuro-stimulation effects themselves.

U.S. Patent Application No. 20140073562 relates to a nasal deliverydevice and method of delivering a substance, preferably comprisingoxytocin, non-peptide agonists thereof and antagonists thereof,preferably as one of a liquid, as a suspension or solution, or a powderto the nasal airway of a subject, preferably the posterior region of thenasal airway, and preferably the upper posterior region of the nasalairway which includes the olfactory bulb and the trigeminal nerve, andpreferably in the treatment of neurological conditions and disorders.

U.S. Pat. No. 8,875,704 described a delivery device and method ofdelivering a powdered substance, in particular a triptan, such assumatriptan, to the posterior region of a nasal cavity of a subject, inparticular for the treatment of headaches, for example, clusterheadaches and migraine, and neuropathic pain. WO 2016133863 provides anasal powder formulation containing glucagon or a glucagon analog fornasal administration, useful in the treatment of hypoglycemia, and inparticular the treatment of severe hypoglycemia. Sherr et al (7)demonstrated in their clinical trials that glucagon nasal powderdelivering glucagon transmucosally might be a promising alternative tointramuscular glucagon in adults and youth with type 1 diabetes,however, the authors did not mention that glucagon can be delivered fromnose to brain.

U.S. Pat. No. 6,462,090, U.S. 20080292713, U.S. 20150010633, U.S.20160354288 and other similar publications described dry powder inhalers(DPI) of therapeutic agents for pulmonary delivery. U.S. 20150010633disclosed the preparation of aerosol formulations of ondansetron usefulexclusively for pulmonary delivery, because the active drug ondansetron,when administered by inhalation, must penetrate deep into the lungs inorder to show physiological action. However, none of the publicationsabove teach or mention the delivery of therapeutic agents to the brainvia intranasal administration. Accordingly, there is an unmet need formethods of treating central nervous system (CNS) disorders with knownand new active agents that provide specific targeting to the CNS (interms of direct administration primarily to the brain), reduce systemicdistribution of the active agents and lower the therapeutically effecteddoses needed for administration.

Opioid overdoses are a worldwide epidemic, affecting both drug abusersand patients treated with prescribed medications. Overdose deaths fromheroin and other opioids represent a significant international publichealth concern, accounting for approximately 106,000 deaths annually(12) and this figure is increasing, particularly in the USA (13).

Opioids intoxication is manifested by reduced consciousness andrespiratory depression which may deteriorate to cardiac arrest anddeath. The antidote naloxone is the drug of choice for treatment ofopioid overdose. Naloxone is a semisynthetic congener of the opioidanalgesic oxymorphone. While the mechanism of action of naloxone is notfully understood, the preponderance of evidence suggests that naloxonehydrochloride is a pure opioid antagonist. It does not possess any“agonistic” or opioid-type properties.

Naloxone is usually administered intravenously (IV) or intramuscularly(IM) with a starting dose of 0.4-2.0 mg and titrated to desiredresponse. Reversal of symptoms is rapid, but acute withdrawal symptomscan be precipitated, particularly in opioid-dependent subjects followingIV administration and higher doses (14). Overall, however, the drug hasan excellent safety profile and, when administered in the absence ofopioids, exhibits little pharmacologic activity (15).

Most of the overdose incidents occur outside the hospitals and requireintervention by unaffected bystanders. Many stakeholders have advocatedprovision of naloxone to people who are not medically trained that arelikely to witness such episodes, thus allowing immediate assistance inthis life-threatening situation (16). This, in fact, has led the WorldHealth Organization (WHO) to issue in 2014 guidelines recommending that‘people likely to witness an opioid overdose should have access tonaloxone’ (17).

This principle was adopted for a nasal liquid spray (Narcan® NasalSpray, Adapt Pharma, PA, USA) having a concentration of 40 mg/mLdelivered in 0.1 mL doses. The bioavailability of the nasal formulationrelative to IM was 0.47 (18). The FDA approved this nasal naloxoneproduct in 201 (19). Another product, Nyxoid 1.8 mg Nasal Spray(Mundipharma Corporation, Ireland) has been authorized for marketing inthe European Union in 2017 (20).

U.S. Pat. No. 9,775,838 (Adapt Pharma & Opiant Pharmaceuticals)describes a method of treating opioid overdose, essentially bydelivering 25-200 μL spray of a pharmaceutical solution comprisingnaloxone, an isotonicity agent and benzalkonium chloride from apre-primed device adapted for nasal delivery into a nostril of apatient, delivering between about 4 mg and about 10 mg naloxone. It isdescribed that the patient experiences a geometric mean naloxone C_(max)not less than about 3 ng/mL following a single spray administration.

U.S. Pat. No. 10,441,538 (Hikma Pharmaceuticals) describes a liquidspray formulation for sublingual and nasal administration comprisingabout 9% w/w naloxone and various excipients, without an isotonicityagent or a buffer. Administration of naloxone in formulations withco-solvents resulted in superior bioavailability. Further, the additionof permeation enhancers such as caprylic acid and benzalkonium chlorideresulted in further increase in bioavailability.

As mentioned above, dry powders have many advantages in intranasal drugdelivery, including improved stability, administration of larger dosesand lack of microbial growth (no need for preservatives).

As shown in the Examples below intranasal of naloxone exhibitedsignificant advantages.

SUMMARY

Disclosed herein is a pharmaceutical composition in a form of dry powderfor intranasal administration, comprising at least one opioid receptorantagonist as active ingredient, said composition comprising a firsttype of solid particles comprising said at least one opioid receptorantagonist and a second type of solid particles comprisingpharmaceutically acceptable disaggregating agent, wherein at least 90%of said first type particles are of a mean particle size of about 10 toabout 30 microns, and less than about 10% of said first type particlesare of a mean particle size equal to or below about 10 microns and saidsecond type particles are of a mean particle size greater than that ofthe first type particles.

In the presently disclosed pharmaceutical composition, less than about5% of said first type particles can be of a mean particle size of orbelow 5 microns, said second type particles are of a mean size of about50 to about 200 microns, for example a mean size of about 50 to about150 microns.

In the presently disclosed pharmaceutical composition, said first typeparticles are of a substantially spherical form and said second typeparticle are of an irregular shape.

The presently disclosed pharmaceutical composition comprises saiddis-aggregating agent as the only excipient for preventing aggregationof the dry powder particles of the active agent and preserving theiroriginal size and shape in said composition.

In the presently disclosed pharmaceutical composition, said at least oneopioid receptor antagonist can be any one of naloxone, naltrexone,almivopan, methylnaltrexone, naloxegon or naldemidine andpharmaceutically acceptable salts thereof and solvates or hydratesthereof, wherein said salt is any of chloride, bromide, oxalate,chloride, or tosylate.

In the presently disclosed pharmaceutical composition, saiddisaggregating agent can be any one of lactose monohydrate, lactose, alactose functional analogue, or any mixture of at least two thereof. Inspecific embodiments, said disaggregating can be any one of dextrose,sorbitol, mannitol, maltitol and xylitol, a cellulose or cellulosederivative, r starch or starch derivative, or any mixture of at leasttwo thereof.

In the presently disclosed pharmaceutical composition, the weight ratiobetween said first type particles and said second type particle can bebetween about 1:9 to about 9:1. The weight ratio between said first typeparticles and said second type particle can between about 1:9 to about9:1. In specific embodiments, the weight ratio between said first typeparticles and said second type particle is from about 1:9 to about 4:6,specifically about 2:8.

In a second aspect, disclosed is a naloxone pharmaceutical compositionin the form of dry powder for intranasal administration, comprising asactive agent naloxone or a pharmaceutically acceptable salt thereof,said composition comprising a first type of solid particles comprisingsaid naloxone or pharmaceutically acceptable salt thereof, and a secondtype of solid particles comprising lactose monohydrate as disaggregationagent, wherein at least about 90% of said first type particles are of amean particle size of about 10-30 microns and less than about 10% ofsaid first type particles are of a mean particle size equal to or belowabout 10 microns and said second type particles are of a mean particlesize greater than that of the first type particles, providing a meteredtherapeutically effective nominal dose of said naloxone orpharmaceutically acceptable salt thereof.

In the presently disclosed pharmaceutical composition of said secondaspect, the weight ratio between said first type particles and saidsecond type particle is from about 1:9 to about 4:6, specifically about2:8.

The pharmaceutical composition of said second aspect, comprises about20% w/w, about 15% w/w, about 10% w/w, about 8% w/w or about 5% w/wnaloxone or said pharmaceutically acceptable salt thereof or solvate orhydrate thereof.

Also disclosed is a disposable dose unit form for single intranasaladministration to a subject of a pharmaceutical composition according toany one of claims 1 to 11, wherein said dose unit is loaded with apredetermined dose of the composition and provides the subject with atherapeutically effective metered dose of said pharmaceutically activeopioid receptor antagonist.

The said disposable dose unit form can be loaded with a predetermineddose of the composition and provides the subject with a therapeuticallyeffective metered dose naloxone or said pharmaceutically acceptable saltthereof.

In some embodiments of the dose unit, the therapeutically effectivemetered dose naloxone or pharmaceutically acceptable salt thereof is 4mg per single administration.

Also disclosed is a for intranasal administration of naloxone comprisingat least one said dose unit for single intranasal administrationcomprising a naloxone pharmaceutical composition as disclosed herein andinstructions for use.

Further disclosed is a method of treating opioid overdose/intoxicationand/or a symptom thereof in a patient in need thereof, said methodcomprising intranasally administering to said patient a therapeuticallyeffective amount of a composition described herein or a single dose of acomposition as contained in the dose unit describe herein.

The said symptom associated with opioid overdose/intoxication is any oneof respiratory depression, central nervous system depression,cardiovascular depression, altered level consciousness, miotic pupils,hypoxemia, acute lung injury, aspiration pneumonia, sedation,hypotension, unresponsiveness to stimulus, unconsciousness, stoppedbreathing; erratic or stopped pulse, choking or gurgling sounds, blue orpurple fingernails or lips, slack or limp muscle tone, contractedpupils, and vomiting. At times, said patient is not breathing.

The single intranasal administration in the disclosed method can providethe patient with a dose of 1.5, 2, 3 or 4 mg naloxone orpharmaceutically acceptable salt thereof.

In the disclosed method of treatment, administration of the at least onedose unit can be repeated at 2 to 3 minute intervals, up to a cumulativedose of from about 8 mg to about 10 mg and up to about 15 mg ofnaloxone.

In some embodiments, the present method of treatment further comprisesadministration of an opioid, that can be administered simultaneouslywith the naloxone or separately.

In the disclosed method of treatment, by the naloxone unit doseintranasal administration the major part of over 50% of the first typenaloxone particles reach turbinates region in the intranasal cavity, andless than 1% of said first type particles reach the lungs of saidpatient.

In specific embodiments, by the naloxone unit dose intranasaladministration at least 85% of the first type naloxone particles reachturbinates region in the intranasal cavity, less than about 10% of saidfirst type naloxone particle reach other region of the intranasalcavity, and less than 1% of said first type particles reach the lungs ofsaid patient.

The pharmaceutical composition of the present disclosure is prepared bya modified spray drying method, for example as shown in FIG. 2 and asdescribed in U.S. patent application Ser. No. 16/636,178, fullyincorporated herein by reference.

Clear superiority of the intranasal composition of the present inventionto the brain and plasma is shown in the Examples below.

Various embodiments may allow various benefits, and may be used inconjunction with various applications. The details of one or moreembodiments are set forth in the accompanying figures and thedescription below. Other features, objects and advantages of thedescribed techniques will be apparent from the description and drawingsand from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Disclosed embodiments will be understood and appreciated more fully fromthe following detailed description taken in conjunction with theappended figures:

FIG. 1 shows the Scanning Electron Microscopy (SEM) image of sumatriptansuccinate agglomerated powder, when the receiving chamber is empty (notprefilled with a diluent or disaggregation agent).

FIG. 2 shows the schematic drawing of the modified spray-dryer apparatusof the embodiments, suitable for the particles engineering andprevention of agglomeration.

FIG. 2a shows Aptar Unitdose Powder device providing a powder dosevolume up to a maximum of 140 mm3, with a dose range between 10-80 mg.

FIGS. 3 and 4 show the SEM images of lactose monohydrate (large cubicparticles or tomohawks comprising “C” and “O” elements) and sumatriptansuccinate particles (small spherical particles comprising also “S”element) of dry powder for intranasal delivery formulation.

FIG. 5 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 3). Two populations of theparticles are clearly seen: the active agent (API) in the range of 5-25microns (μm) and lactose in the range of 50-200 microns; D(10)=11.6 μm;D(50)=95.4 μm; D(90)=155 μm.

FIG. 6 shows the particle size distribution of the API in thepharmaceutical composition of the embodiments (see Example 3). The meanparticles size is 12 μm.

FIG. 7 shows the SEM image (X100) of the mixture of lactose monohydrate(large polyhedrons) and alprazolam in the dry powder composition of theembodiments for intranasal administration.

FIG. 8a shows the SEM image (X1200) of lactose monohydrate (largepolyhedrons) and alprazolam (small polyhedrons) of the dry powdercomposition of the embodiments for nasal administration formulation.

FIG. 8b shows the X-ray elemental analysis of the large polyhedronsconfirming that these are the particles of lactose monohydratecontaining “C” and “O” atoms.

FIG. 8c shows the X-ray elemental analysis of the small polyhedronsconfirming that these are the particles of alprazolam containing “C”,“O” and “Cl” atoms.

FIG. 9 shows the SEM images (X600) of the mixture of lactose monohydrate(large polyhedrons) and oxycodone hydrochloride (small non-aggregatedspheres) in the dry powder composition of the embodiments for intranasaladministration.

FIG. 10 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 14). Two populations ofparticles is clearly seen: oxycodone hydrochloride in the range of 3-30μm and lactose in the range of 50-200 μm. D(10)=57.4 μm; D(50)=97.3 μm;D(90)=151 μm;

FIG. 11 shows the SEM image (X2400) of lactose monohydrate (largepolyhedrons) (Particle 1) and insulin-sodium chloride (small sphericalshape) (Particles 2, 3, 4 and 5) of the dry powder composition forintranasal administration.

FIG. 12 shows the X-ray elemental analysis of Particle 2 containing “C”,“O” and “S” atoms of insulin molecules and “Na” and “Cl” atoms of thesodium chloride salt.

FIG. 13 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 19). Two populations of theparticles are clearly seen: insulin-sodium chloride particles in therange of 5-35 μm and lactose in the range of 50-200 μm. D(10)=57.4 μm;D(50)=97.3 μm; D(90)=151 μm.

FIG. 14 shows the oxycodone pharmacokinetic profiles in rat's plasmafollowing administration of oral gavage (oral) and intranasal powder(intranasal) to 12 SD rats at dose of 10 mg/kg.

FIG. 15 shows the oxycodone pharmacokinetic profiles in rat's brainsfollowing administration of oral gavage (oral) and intranasal powder(intranasal) to 12 SD rats at dose of 10 mg/kg.

FIG. 16 shows the SEM images of lactose monohydrate (large shapelessparticles) and naloxone hydrochloride particles (small sphericalparticles) of dry powder for intranasal delivery formulation (seeExample 27).

FIG. 17 shows the particle size distribution of the pharmaceuticalcomposition of the embodiments (see Example 28). Two populations of theparticles are clearly seen: the Naloxone HCl active agent in the rangeof 5-30 microns (μm) and lactose in the range of 40-240 microns;D(10)=10.1 μm; D(50)=78.6 μm; D(90)=148 μm.

FIG. 18 shows XRD pattern images for Lactose Monohydrate, Naloxone HCland Naloxone HCl microparticles (see Example 32)

FIG. 19 shows XRD pattern images for Initial Naloxone microsphere powder(lower) and stored for 6 months (upper) (see Example 32)

FIG. 20 shows the Mean Plasma Total Naloxone Concentration-Time Profile(Linear Scale)

FIG. 21 shows the Mean Plasma Unconjugated Naloxone Concentration-TimeProfile (Linear Scale) (Example 33)

FIG. 22 shows the percentage deposition of Naloxone in each region ofinterest in the Nasal Cast (Example 34)

DETAILED DESCRIPTION

In the following description, various aspects of the present applicationwill be described. For purposes of explanation, specific configurationsand details are set forth in order to provide a thorough understandingof the present application. However, it will also be apparent to oneskilled in the art that the present application may be practiced withoutthe specific details presented herein. Furthermore, well-known featuresmay be omitted or simplified in order not to obscure the presentapplication.

The terminology used herein is for describing particular embodimentsonly and is not intended to be limiting of the invention. The term“comprising” and “comprises”, used in the claims, should not beinterpreted as being restricted to the components and steps listedthereafter; they do not exclude other components or steps. They need tobe interpreted as specifying the presence of the stated features,integers, steps and/or components as referred to, but does not precludethe presence and/or addition of one or more other features, integers,steps or components, or groups thereof. Thus, the scope of theexpression “a composition comprising A and B” should not be limited tocompositions consisting only of components A and B. Also, the scope ofthe expression “a method comprising the steps X and Z” should not belimited to methods consisting exclusively of those steps.

Unless specifically stated, as used herein, the term “about” isunderstood as within a range of normal tolerance in the art, for examplewithin two standard deviations of the mean. In one embodiment, the term“about” means within 10% of the reported numerical value of the numberwith which it is being used, preferably within 5% of the reportednumerical value. For example, the term “about” can be immediatelyunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. In other embodiments, theterm “about” can mean a higher tolerance of variation depending on forinstance the experimental technique used. Said variations of a specifiedvalue are understood by the skilled person and are within the context ofthe present invention. As an illustration, a numerical range of “about 1to about 5” should be interpreted to include not only the explicitlyrecited values of about 1 to about 5, but also include individual valuesand sub-ranges within the indicated range. Thus, included in thisnumerical range are individual values such as 2, 3, and 4 andsub-ranges, for example from 1-3, from 2-4, and from 3-5, as well as 1,2, 3, 4, 5, or 6, individually. This same principle applies to rangesreciting only one numerical value as a minimum or a maximum. Unlessotherwise clear from context, all numerical values provided herein aremodified by the term “about”. Other similar terms, such as“substantially”, “generally”, “up to” and the like are to be construedas modifying a term or value such that it is not an absolute. Such termswill be defined by the circumstances and the terms that they modify asthose terms are understood by those of skilled in the art. Thisincludes, at very least, the degree of expected experimental error,technical error and instrumental error for a given experiment, techniqueor an instrument used to measure a value.

As used herein, the term “and/or” includes any combinations of one ormore of the associated listed items. Unless otherwise defined, all terms(including technical and scientific terms) used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. It will be further understood that terms,such as those defined in commonly used dictionaries, should beinterpreted as having a meaning that is consistent with their meaning inthe context of the specification and relevant art and should not beinterpreted in an idealized or overly formal sense unless expressly sodefined herein. Well-known functions or constructions may not bedescribed in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on”,“attached to”, “connected to”, “coupled with”, “contacting”, etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on”, “directly attached to”, “directly connectedto”, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

The terms “active agent”, “pharmaceutical active agent”, “active”,“API”, “active pharmaceutical ingredient”, “active substance”, “activemolecule”, “active compound” or “drug” are used interchangeably.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealised or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

In one aspect, disclosed herein is a pharmaceutical composition forintranasal administration in the form of dry powder, comprising at leastone opioid receptor antagonist as active ingredient, the compositioncomprising a first type of solid particles comprising the at least oneopioid receptor antagonist and a second type of solid particlescomprising pharmaceutically acceptable dis-aggregating agent, wherein atleast 90% of said first type particles are of a mean particle size ofabout 10 to about 30 microns, and less than about 10% of said first typeparticles are of a mean particle size equal to or below about 10 micronsand said second type particles are of a mean particle size greater thanthat of the first type particles. In specific embodiments of this aspectof the present disclosure less than 5% of said first type particles areof a mean particle size of less than 5 microns. The first type particlesare of substantially spherical form. The second type particles are ofirregular form and of a size of about 50 to about 200 microns.

In embodiments of this aspect of the present disclosure, the opioidreceptor antagonist is any one of naloxone, naltrexone, almivopan,methylnaltrexone, naloxegon or naldemidine, but not limited thereto, andpharmaceutically acceptable salts thereof, and hydrates and solvates ofthese salts. Exemplary salts are bromides for example, methylnaltrexonebromide, oxalates, for example naloxegon oxalate, chlorides for examplenaloxone HCl, tosylates, for example naldemidine tosylate, and othersare possible. Within the context of this disclosure “naloxone” is to betaken to mean also pharmaceutically acceptable salts of naloxone, forexample but not limited those slats mentioned above, with naloxonehydrochloride, in anhydrous or solvated or hydrated form thereof as aspecific example.

In specific embodiments of this aspect of the present disclosure, theopioid receptor antagonist is naloxone hydrochloride.

The terms opioid receptor “antagonist” and “inverse agonist” may be usedherein interchangeably.

The terms “opioid” or “opiate” as used herein is to be taken to mean atleast one of natural or synthetic or semi-synthetic narcotics, includingcodeine, fentanyl, heroin, hydromorphone, meperidine, methadone,morphine and derivatives, oxymorphone, oxycodone HCl, hydrocodonebitartrate, hydromorphone, opium and drugs such as tramadol andtapentadol, as well as others.

The disaggregating agent comprised in the disclosed composition is aninert carrier, as described in detail below. It is to be noted that“disaggregating agent”, “carrier”, “diluent” and “deagglormeratingagent” are used herein interchangeably, and refer to an inert ingredientadded to the pharmaceutical composition, comprising the said second typeparticles.

The intranasal compositions comprising an opioid receptor antagonistaccording to the present disclosure is prepared according to the methodsdescribed herein. The preparation of a specific composition is describedin the Examples below. Example 26 describes the preparation of naloxonehydrochloride composition with lactose monohydrate as the disaggregatingagent. SEM imaging of the composition is shown in FIG. 16. The particledistribution of the composition of Example 26 is described in Example 28and shown in FIG. 17.

In specific embodiments, the naloxone compositions prepared according tothe herein described methods, can be designed for desired naloxonelevels, for example a level of at least about 22.2% w/w naloxonehydrochloride or a hydrate thereof in the form of microspheres when saidmicrospheres are separated and dis-agglomerated by at least 77.8% oflactose monohydrate particles. In the composition exemplified in Example26, the loading of naloxone hydrochloride obtained was about 26% w/w.The obtained compositions can be diluted by mixing with a further amountof the disaggregating agent (lactose monohydrate in Example 26), to givea desired level of naloxone hydrochloride. This additional mixing isincluded in the general process described herein. Thus, for example, inExample 26 the crude product was mixed with an additional amount oflactose monohydrate, to give a product with final level of 20% w/wnaloxone hydrochloride. This final composition was then introduced intoa disposable dose device, as described below, to provide a dose of fromabout 4 to about 12 mg naloxone hydrochloride upon single intranasaladministration.

The pharmaceutical composition according to the present disclosure canbe contained in disposable dose units for intranasal administration,providing predetermined metered dose of naloxone, specifically naloxonehydrochloride. An example of such dose unit is illustrated in FIG. 2A,which shows Unit Dose Powder Device (UDS), manufactured by Aptar Pharma.Devices of this type for powder spraying are user friendly and designedto enable systemic delivery of small and accurately metered doses ofdrug formulations by patients or caregivers who are not healthcareprofessionals or medically trained.

The present disclosure further relates to a dose unit form (alsoreferred to as dose unit device, dose device or drug device),specifically a disposable dose unit form, for intranasal administrationto a subject of a single dose of a\the pharmaceutical compositionaccording to the present disclosure, which comprises as activeingredient an opioid receptor antagonist, specifically naloxone orpharmaceutically acceptable salts thereof such as naloxonehydrochloride, wherein the dose unit is loaded with a predetermined doseof the composition and provides the subject with a metered dose thepharmaceutically active ingredient comprised in the composition. Thepreparation of naloxone hydrochloride dose units is described in Example29. The dose units prepared each contained a total of 20 mg composition,of which 4 mg were naloxone hydrochloride (200 mg/g). Dose uniformitywas tested for 10 dose units, as described in Example 30. As shown inExample 31, the dose unit devices loaded with combination exhibited goodproduct stability under normal and accelerated (at about 40° C. and 75%relative humidity) storage conditions. Importantly, although devoid ofpreserving agents, the present dose unit forms are storage stable. Inaddition to the dose unit devices described above and in the Examplesand drawing, the naloxone composition of the present disclosure can beadministered using syringe-driven device and pump-driven sprayingatomizers. Bi-dose and multiple-dose administration devices are alsocontemplated within the scope of the present invention.

Surprisingly, the naloxone contained in the dose devices of the presentdisclosure was retained in amorphous form, as shown in Example 32 andFIGS. 18 and 19.

Compositions according to this aspect of the invention which containnaloxone or pharmaceutically acceptable salt thereof as the activeopioid receptor antagonist and dose units thereof are also referred toherein as naloxone compositions, respectively naloxone dose units.

The naloxone compositions of the present disclosure are particularlyintended for treatment of opioid overdose and acute opioid overdose,also referred to as opioid intoxication, which is described in detailabove. Treatment of opioid overdose as referred to herein is to be takento mean alleviating or reversing the effects of the opioid overdose, aswell as symptoms associated therewith such as depression and even lossof consciousness and respiratory depression, and any condition that isresponsive to and can be ameliorated by administration of opioidreceptor antagonists, such as various intoxications, for example afterexposure to nerve gas (naloxone induced long-lasting analgesia in miceexposed to sarin and soman (21)). The naloxone compositions and doseunits thereof according to the present disclosure have been shown to besignificantly effective.

Example 33 presents the results of a comparative pharmacokinetic study,which compared the bioavailability and bioequivalence of a naloxonecomposition according to the present invention (Microspheres NasalPowder, also referred to herein as FMXIN001) providing 4 mg naloxone persingle administration, and the commercially available “NARCAN®”, aliquid nasal spray, a Nasal Spray also providing 4 mg naloxone persingle administration. FIG. 20 shows the Mean Plasma Total NaloxoneConcentration-Time Profile (Linear Scale) and FIG. 21 shows the MeanPlasma Unconjugated Naloxone Concentration-Time Profile (Linear Scale).

Clear superiority of the powder intranasal spray composition of thepresent invention compared to the NARCAN® liquid intranasal is shown.These results are particularly surprising considering that bothcompositions were nasally administered in the same dose of 4 mg naloxonehydrochloride.

Notably, the present naloxone composition is devoid of permeationenhancer or other additives that can enhance absorption, as described inthe prior art (e.g. U.S. Pat. No. 10,441,538, supra).

A naloxone unit according to the present disclosure can contain fromabout 1.5 to about 15 mg of the active naloxone or naloxone salt.

As shown in Example 34, when the naloxone intranasal powder formulationin accordance with the present disclosure was administered by means of aunit dose device for intranasal administration as described herein (byAptar), loaded with the formulation, a high proportion of the naloxoneparticle of at least 86% reached the nasal turbinates region, morespecifically about 35% were the middle part and 51% in the upperolfactory area, while less than 10% of the naloxone particles were inthe nose and less than 1% reached the lungs, providing at treatedsubject with very high effective amounts of naloxone and improvedtherapeutic effect.

Still further, provided herein is a kit for the treatment/reversal ofopioid overdose. The kit comprises at least one dose unit of naloxonepowder composition as disclosed herein and instructions for use. Thedose unit can be single-dose, bi-dose or multiple-dose unit.

In one embodiment, a pharmaceutical composition in a form of dry powderfor intranasal (nose-to-brain) N2B administration to a patient in needthereof comprises solid particles of at least one active agent and solidparticles of a diluent, said pharmaceutical composition beingsubstantially free of excipients other than the solid diluent, whereinsaid pharmaceutical composition having at least 90% of the particles ofsaid at least one active agent with a mean particle size of 10-30microns and less than 10% of the particles of said at least one activeagent with a mean particle size equal to or below 5 microns, and havingthe particles of said diluent with a mean particle size of 50-200microns.

The composition of the embodiment is essentially free of any excipientsother than the solid diluent, such as lactose monohydrate or a lactosefunctional analogue. In another embodiment, a pharmaceutical compositionin a form of dry powder for intranasal administration by transmucosalsystemic delivery via the upper nose mucosa (the turbinate and lymphoidtissues located at the back of the nasal cavity) of a compositioncomprises an active agent having a mean particle size in the range of10-30 microns, wherein at least 90% of its particles have a meanparticles size of not less than 5 microns and not more than 30 microns,and a diluent having a mean particle size in the range of 50-200microns. As noted above, the diluent is also used for preventingaggregation of the dry powder particles containing at least one activeagent.

At first sight, it would seem that the larger particle size might leadto a relatively lower N2B bioavailability of the active agent. However,this is offset by the better absorption of the larger particles of theactive agent in the present invention, due to the longer residence timeof the active on the nasal mucosa. Thus, a double advantage is obtainedby administration of the dry powder composition of this specificparticle size range: on one hand, better absorption of the active agent,and on the other hand, this mode of administration using delivery ofrelatively large particles directly to the upper region of the nasalcavity is substantially free of systemic effects due to lung delivery.In a further embodiment, the pharmaceutical composition for intranasalN2B administration comprises an active agent having a particle size inthe range from about 10 microns to about 30 microns, and more than 90%particles of the active agent are above 5 microns, and wherein theactive agent is delivered to the superior region of the nasal cavity. Inyet further embodiment, the composition comprises an active agent havinga mean particle size range of 10-30 microns, wherein at least 90% of itsparticles have a mean particles size of not less than 5 microns and notmore than 30 microns, and a diluent with a particle size in the range of50-200 microns, said composition may be administered either bynose-to-brain (N2B) delivery or by systemic delivery, or both.

In some embodiment, the intranasal delivery method of the presentapplication provides delivery of dry powders to the nasal mucosa,olfactory region, the trigeminal nerve and other structures of thelimbic system. In another embodiment, the pharmaceutical composition isused to deliver the active agent to the upper region of the nasalcavities. This upper region represents the only region where it ispossible to circumvent the blood-to-brain barrier and enable transportto the cerebrospinal fluid (CSF) and the brain.

The composition of the embodiments may be delivered by any one of theknown in the art nasal devices, such as pressurised devices, dry powdersprayers or bi-directional nasal devices. Multi-dose devices as well assingle-dose devices may be used.

In some embodiments, the desired attributes for an intranasal powderformulation with commercial potential required in EMA and FDA Guidelines(8) are inherent features of the compositions of the embodiments. Theuniform dose deliverability of the initial and stored formulation by adevice for intranasal administration is exemplified in Example 22. Noneof the dose measurements was found to be outside 75-125% of the labelclaim.

The present application provides an apparatus and a method for themanufacture of a pharmaceutical composition in a form of dry powder forintranasal delivery having less than 5% of small particles below 5microns, to exclude undesirable administration to the lungs. FIG. 2schematically shows the apparatus for the preparation of thepharmaceutical composition of the embodiments in a dry powder form, saidapparatus comprises the following components:

-   a) A spray-drying chamber [1] capable of spray-drying a clear and    homogeneous solution of at least one active agent to obtain dry    powder particles of said at least one active agent in a moist air,    said solution being free of diluent;-   b) A cyclone separator [2] capable of receiving said dry powder    particles and the moist air stream from said spray-drying chamber    [1], separating said particles from the moist air through vortex    separation, exhausting the air and transferring the separated    particles to a receiving chamber [3] through a bag filter; and-   c) The receiving chamber [3] (or “receiver”) pre-filled with a    diluent and adapted for receiving the separated dry powder particles    from the cyclone separator [2], mechanically stirring and    homogenising said particles with the diluent to obtain the    pharmaceutical composition in the dry powder form of the    embodiments; wherein said diluent is capable of colliding and    continuous in-situ blending with the particles during the stirring    in the receiving chamber [3], thereby preventing their aggregation    and preserving their original size and shape.

The spray-drying chamber is equipped with nozzles, which are used toproduce droplets of the active agent solution, to control the dropletand powder particle size and to maximise heat transfer and the rate ofsolvent vaporisation. The spray-dryer apparatus of the embodiments thusreceives a stream of the liquid solution containing the active agent,sprays it through the nozzles into a hot gas stream, such as nitrogen orair, and removes the solvent as a vapor. As the moisture quickly leavesthe droplets, the dry powder is produced. The droplet size may rangefrom 20 to 180 μm, depending on a particular nozzle used. In the presentembodiments, the sprayed solution of the active agent is free of anydiluent.

The nozzles are designed to spray the solution of the active agent intoa hot air flow, thereby achieving a thorough mixing and uniformdistribution of the hot air flow and sprayed solution in thespray-drying chamber to produce a substantially complete evaporation ofliquids and drying of solid particles of the active agent from themixture throughout said chamber. In a specific embodiment, thespray-drying chamber is equipped with a two-fluid nozzle having anappropriate opening controlling the API particles size in the range of10-30 μm. One of the fluids is an active agent solution, free of anydiluent, and the other fluid is a drying gas or air.

At the laboratory scale, the stirring and homogenisation is achieved byusing a magnetic stirrer and a magnetic bar of appropriate size, inaddition to the rotation of the receiving chamber. At industrial scale,the stirring and homogenisation may be achieved by using a mechanicalstirrer of appropriate size and form, or moving, rotation and vibrationof the whole receiving chamber. A conventional spray-drying apparatuscontains the empty receiving chamber collecting the dry powder particlesof an active agent. This receiver is emptied from time to time in orderto ensure the continuous process. In contrast, the present applicationdiscloses the receiving chamber pre-filled with a continuously stirreddiluent for preventing aggregation of the dry powder particles andpreserving their original size and shape.

The method for the preparation of the pharmaceutical composition of theembodiments in a dry powder form is based on the spray-drying processrapidly drying the solution of at least one active agent, free of anydiluent or excipient, with hot air, thereby producing a dry powder ofthe active agent. This method comprises the following steps:

-   A. Preparing a clear and homogeneous solution of at least one active    agent in an organic solvent or solvent mixture, in a solvent-water    or water miscible solvent mixture, or in water.-   B. Filling the receiving chamber with a diluent and continuously    stirring the diluent in the receiving chamber;-   C. Streaming the solution prepared in step (A) together with hot gas    to the spray-draying chamber, spray-drying the solution in the    spray-drying chamber to obtain dry powder particles of said at least    one active agent in a moist gas, and transferring the obtained dry    powder particles and the moist gas stream to the cyclone separator;-   D. Separating said particles from the moist gas through vortex    separation in the cyclone separator, exhausting the gas and    transferring the separated particles to the receiving chamber    through a bag filter;-   E. Stirring and homogenising said particles received from step (D)    with the diluent in the receiving chamber to obtain the    pharmaceutical composition of the embodiments in the dry powder    form; wherein said diluent is capable of colliding and continuous    in-situ blending with the particles during the stirring in the    receiving chamber, thereby preventing their aggregation and    preserving their original size and shape; and-   F. Adding diluent and additionally mixing of the pharmaceutical    composition obtained in step (E) with the additional amount of the    diluent to achieve the desired active agent-to-diluent ratio in said    pharmaceutical composition.

The gas used in the spray-drying process is normally air. However, ifthe solvent is flammable, for example ethanol, or the product isoxygen-sensitive, then nitrogen or any other suitable inert gas may beused instead.

In a particular embodiment, the clear and homogeneous solution of theactive agent is obtained by dissolving an active agent either as a freebase or as a salt in an organic solvent, a mixture of two or moreorganic solvents or in water. The gas outlet temperature in the methodof the embodiments is generally about 75° C. or below, preferably about70° C. or below, more preferably about 59° C. or below, yet morepreferably about 52° C. or below, or about 50° C. The gas inlettemperature is generally about 75° C. or higher, preferably about 80° C.or higher, more preferably about 90° C. or higher, yet more preferablyabout 100° C. or higher, even more preferably about 110° C. or higher,or about 120° C. The volatile products obtained in the process are theorganic solvents and/or water. The volume of water should be 50% or moreof the volume of the volatiles. In the specific embodiment, a Class 3organic solvent is used in the method for the preparation of thepharmaceutical composition in a dry powder form. The residual solventcontent after drying is less than 0.5%.

The drug (active agent) content of the composition of the embodimentsmay be adjusted so as to provide the total dose of the drug required toachieve the therapeutic effect as a single dose in a single nostril. Thedrug administration can be repeated in the second nostril in order todouble the amount of the active material. Stability of the compositionof the embodiments on storage was determined under accelerated andambient conditions.

The device used for the intranasal delivery of the compositions of theembodiments may be engineered so as to provide the appropriate plumegeometry and spray pattern of initial and stored compositions. In someembodiments, these compositions may have a narrow particle sizedistribution with median diameter between 10 to 20 microns.

The shape and particle morphology of the dry powder of the embodimentsfor intranasal delivery were characterized using an electron microscope.Reference is now made to FIGS. 8a-8c and Example 13 (in the experimentalsection below) showing the polyhedron shape of the particles. FIGS. 3,4, 9 and 11 show spherical particles, contribution of which may be moresignificant in reaching the deeper region of the nasal passage.

The process of the embodiments for the preparation of the pharmaceuticalcomposition of the present embodiments in a dry powder form for nasaldelivery produces preponderantly a spherical population of particles. Inrare cases, the active agent may form a polyhedron-shape crystallineparticles or spherical/polyhedron mixtures.

Many previous attempts at developing an intranasal powder formulationfell short in one or several of the desired properties includingsatisfactory safety and tolerability profile. The compositions of theembodiments are designed to have some or all of these desiredproperties. These compositions have two required components:

-   (a) The active agent may be hydrophilic or lipophilic active agent,    wherein the hydrophilic active ingredient may be delivered via    olfactory mucosa to the brain and the lipophilic active agent may be    delivered via nasal mucosa to systemic circulation and then to the    brain, bypassing the liver.-   (b) Lactose monohydrate or a lactose monohydrate functional analogue    also used for preventing aggregation of the active agent particles    and preserving their original size and shape.

The active agent of the embodiments is a hydrophilic or lipophilic,chemical or biochemical, solid therapeutic substance selected fromcompounds for use in common cold treatment, anti-addiction agents,anti-infective agents, analgesics, anaesthetics, anorexics,antarthritics, anti-allergy agents, antiasthmatic agents,anticonvulsants, anti-depressants, antidiabetic agents,anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-hypertensive agents, anti-inflammatory agents, antimigrainepreparations, anti-motion sickness preparations, antinauseants,antineoplastics, anti-obesity, antiosteoporosis, anti-Parkinsonismdrugs, antipruritics, antipsychotics, antipyretics, anticholinergics,benzodiazepine antagonists, bone stimulating agents, central nervoussystem stimulants, hormones, hypnotics, immunosuppressants,prostaglandins, proteins, peptides, polypeptides and othermacromolecules, psychostimulants, compounds for use in rhinitistreatment, compounds for use in sexual hypofunction treatment,sedatives, compounds for use in treatment of known or suspected opioidoverdose, tranquilizers and vitamins, probiotics, natural ingredients,peptide or protein therapeutic agents such as cytokines, hormones,clotting factors, vaccines, monoclonal antibodies, amino acids, or anycombination thereof.

In some embodiments, the active agent is selected from sumatriptansuccinate, zolmitriptan salts, naratriptan, rizatriptan, almotriptan,eletriptan, frovatriptan, bupivacaine, fibroblast growth factor,cephalexin, lidocaine, clobazame, midazolam, alprazolam, diazepine,lorazepam, dexmedetomidine, monosialoganglioside, cocaine, insulin,glucagon, oxytocin, fentanyl, sulfentanil, diamorphine, ketamine,apomorphine, buprenorphine, morphine sulphate, oxycodone hydrochloride,butorphanol, NSAIDs, paracetamol, benzodiazepines, dopamine,pramipexole, rasagiline, rogitine, ondansetron, granisetron,metoclopramide, naloxone, naltrexone, atropine, adrenaline, cannabisactive compounds, epinephrine, isosorbide dinitrate, obitoxine,dexmedetomidine, metoclopramide, L-dopa, nicotine, sildenafil,nafarelin, dobutarnine, phenylephrine, tramazoline, xylometazoline,tramadol, methacholine, ipratropium, scopolamine, propranolol,verapamil, hydralazine, nitroglycerin, clofilium tosylatecannabis activecompounds and pharmaceutically acceptable salts, isomers, and mixturesthereof.

In a specific embodiment, the dry powder of the active agent for nasaldelivery contains at least 90% of the particles having a mean particlesize of 10-30 microns, and less than 10% of the particles having a meanparticle size equal to or below 5 microns. The particle size is measuredusing the laser diffraction method. The active agent particles may havespherical, ellipsoid, polyhedron, cubic, plate, or needle shapes. Thepreferable particle shapes are spherical and ellipsoid. These shapesprovide the best aerodynamic properties of the active agents. The drugparticle shape and morphology is determined using the electronmicroscopy.

The solid diluent of the embodiments is selected from lactosemonohydrate or a lactose monohydrate functional analogue, such aslactose, cellulose and derivatives, starch and derivatives, dextrose,sorbitol, mannitol, maltitol, xylitol or mixtures thereof. The preferredsolid diluent is lactose monohydrate.

Lactose may be present in the form of α-lactose monohydrate, anhydrousβ-lactose or amorphous lactose. α-Lactose monohydrate is a commonly usedDPI (dry powder inhaler) excipient, and is a pharmacopeia excipient forDPIs in a pulmonary delivery route. Lactose monohydrate of theembodiments has a bulk density of 0.6-0.8 g/ml and partlytomahawk-shaped crystals with the following particle size distribution:D₁₀ 30-60 μm; D₅₀ 70-110 μm and D₉₀ 110-150 μm.

According to Jagdeep Shur et al, “From single excipients to dualexcipient platform in dry powder inhaler products”, InternationalJournal of Pharmaceutics (2016), 514, pages 374-383, the singleexcipient platform (SEP) has been the most prevalent excipient strategyused in many commercial DPI products. The majority of approved SEP DPIproducts have been developed based on the well-known ‘carrier’ approach.The role, or functionality, of the single excipient in the SEP-based DPIproducts has traditionally been described as a ‘dispersant’, ‘filler’,‘diluent’ or ‘carrier’. The ‘carrier’ description is now so commonplacein academic, industrial and regulatory circles that in 2014 it wasincorporated into the updated respiratory section of the United StatesPharmacopoeia (General chapter 1059). Such ‘carrier’ excipients, oftenof a small particle size, are also used in what are described as‘agglomerate’ formulations. This is in contrast to the large particlesize (50-200 microns) of lactose or lactose functional analogue of theembodiments. Thus, unlike the regular DPIs, the excipient of theembodiments (such as lactose or lactose functional analogue) has ratherlarge particle size (50-200 microns), and—while being multi-functional,it is mainly used as a diluent and carrier for preventing agglomerationof much smaller particles of an active agent, deagglomeration of theparticles and homogenisation of the composition. Therefore, theexcipient of the embodiments is referred to throughout the presentapplication as “diluent”.

It is a surprising and unexpected finding that the lactose monohydratesolid diluent of the embodiments may serve for preventing aggregation oragglomeration of the active agent particles, or as a disaggregant orde-agglomerating agent in the preparation of the dry powder compositionfor intranasal administration, when the spray-dried active agent and thediluent are mixed in-situ in the receiving chamber of the spray-dryingapparatus. It is indeed unpredictable and surprising that the largeparticles of lactose monohydrate with a mean diameter of 50-200 μm arecapable of preventing the aggregation of the small active agentparticles with a mean diameter of 10-30 μm. The lactose monohydrateparticles cannot therefore enter the nasal passage and become swallowedafter actuation.

Thus, the compositions of the embodiments comprise at least one activeagent and a diluent, such as lactose or a lactose functional analogue,and are substantially free of other excipients, such as surfactants,lipid agents, solvents or propellants. Most of the DPI formulations relyon lactose monohydrate as a diluent. However, lactose cannot be used inthe compositions comprising active compounds that interact with thereducing sugar function of lactose in the Maillard reaction. Lactosefunctional analogues of the embodiments, which may be used as a soliddiluent instead of lactose and may replace lactose in some compositions,particularly as an alternative for patients suffering from lactoseintolerance, are selected from cellulose and derivatives, starch andderivatives, mannitol, glucose, sorbitol, maltitol, xylitol or mixturesthereof. The particle size of these diluents is also in the 50-200 μmrange.

The pharmaceutical composition of the embodiments may further compriseone or more pharmaceutically acceptable diluents, excipients or both.The pharmaceutical composition of the embodiments may be prepared in theform of a powder, simple powder mixtures, powder microspheres, coatedpowder microspheres, liposomal dispersions or combinations thereof.

The conventional spray drying process uses an empty receiving chamber inthe beginning of the process. Such receiving chamber is filled with thespray-dried product powder and emptied from time to time in order toensure the continuous process. In the present embodiments, the receivingchamber is however pre-filled with the continuously stirred diluent forpreventing agglomeration or de-agglomeration of the active agentparticles. The regular methods for the preparation of dry powders fornasal delivery usually use surfactants and lipid agents fordisaggregation and de-agglomeration of the solid particles and forpreventing their aggregation. It was surprisingly and unexpectedly foundthat rather coarse particles of the diluent, such as lactose or lactosefunctional analogue, with the size range of 50-100 μm preventaggregation of the active agent particles having the size range of 10-30μm. In a further embodiment, a method for disaggregation andde-agglomeration of the active agent dry powder and for preventing itssolid particles aggregation comprises in-situ mechanical mixing of theagent dry powder with a diluent, preferably lactose monohydrate, in thereceiving chamber of the spray-drying apparatus of the embodiments.

The active agent for nasal inhalation in a dry powder form is usuallyproduced by jet or wet milling techniques that give rise to broadparticle size distribution and to non-spherical and non-uniform shapesof the particles. In addition, the jet or wet milling methods produceparticles of less than 5 μm. These coarse inhalable particles of lessthan 5 μm may easily reach the lungs by nasal spraying (with a nasalspraying device) or by inhaling (with an inhalation device) and causetiny wounds and scarring to the lungs: each time this happens, it causesa very small amount of irreversible damage. The immediate effect isunnoticeable, but over some periods of time, this can result insignificantly decreased lung capacity, and a number of other healthissues. Therefore, production of the dry powder particles ranging from2-10 μm, particularly less than 5 μm, for the intranasal administrationshould be avoided by all means. The present application providessolution also to this problem by disclosing the method for thepreparation of the active agent particles of the embodiments having aspherical shape with a narrow size distribution (10-30 μm), which aresafe for use in nasal spraying or inhaler devices.

In some embodiments, there is provided a mode of administration of anactive agent by nasal delivery, wherein the active agent has a particlesize more than 10 μm and a narrow size distribution range, the particlesare substantially spherical or ellipsoid and the composition comprisingthis active agent is administered by a spraying with a nasal sprayingdevice or inhaling with an inhaler device.

As described above, the preparation method of the embodiments ischaracterised by the two major steps: the drying, more preferablyspray-drying, of the active agent clear and homogeneous solution, andthen mixing the obtained dry powder with the solid diluent, such aslactose or lactose functional analogue, thereby obtaining thecomposition of the embodiments in a form of dry powder consisting of anactive agent and a solid diluent, said composition having a particlesize ranging from 10 to 30 μm and a spherical shape of the drugparticle. This is in contrast to spray-drying processes described in thepatent documents U.S. Pat. No. 6,462,090, U.S. 20080292713, U.S.20150010633 and U.S. 20160354288, which yield the composite active agentparticles with the particle size less than 5 μm. The spray-drying stepin the process of the embodiments yields active agent particles largerthan 10 μm. These particles are then in-situ blended with the soliddiluent, such as lactose, to prevent the growth of the particles andtheir agglomeration.

The compositions of the embodiments for intranasal administrationcontaining the active compounds, such as analgesics, opioids or triptansmay be used for the fast and efficient pain relief.

To sum up, in some embodiments, there is provided a pharmaceuticalcomposition, wherein the solid diluent is the only excipient, said soliddiluent is used for prevention of active agent aggregation in saidcomposition. In some embodiments, there is provided a pharmaceuticalcomposition, wherein the dry powder particles of the active agent aresubstantially in a spherical form. In some embodiments, atherapeutically effective dose of the pharmaceutical composition of theembodiments may be intranasally administered to a patient in needthereof, wherein the administration is targeted at the uppermost regionof the nasal cavity, thereby resulting in the nose-to-brain (N2B)delivery of the active agent to the brain of the patient, or in thetransmucosal systemic administration. In some embodiments, there isprovided a method of treatment, wherein the administration delivers anentire therapeutically effective dose of at least one active agent toone nostril. In some embodiments, there is provided a method oftreatment, wherein the therapeutically effective dose of at least oneactive agent is administered once daily. In some embodiments, there isprovided a method of treatment, wherein the therapeutically effectivedose of at least one active agent is lower than the therapeuticallyeffective dose of a similar intranasal composition using a non-N2B modeof delivery.

The significantly improved pharmacokinetic profile and superior effectsof the intranasal composition of the present invention on the brain andplasma compared to the oral solution are shown in the in-vivoexperiments (see Example 24, and FIGS. 14-15). The faster onset ofaction and higher drug concentration in plasma were demonstrated for theintranasal powdered composition of the present invention compared to theoral solution. In addition, the faster onset of action and highersustained drug concentration in brain was demonstrated for theintranasal powdered composition of the present invention compared to theoral solution.

In particular and specific embodiments, the present disclosure providesmethods and drug delivery devices (as used and disclosed herein) fortreating overdoses opioid/s as defined herein, by intranasaladministration to a patient in need of a composition according to thepresent disclosure. In embodiments of the presently disclosed methods,administration can be into one or both nostrils of the patient.

The administration of the opioid antagonist, specifically naloxone,leads to titrating opioid receptor occupancy, and thus the presentlydisclosed methods can be used for titrating opioid receptor occupancy.The presently disclosed methods of treating opiate overdose, can lead tocomplete reversal of an opioid overdose.

Further disclosed herein are methods for lowering opioid overdose riskin a subject at risk for opioid overdose. In these methods, thepresently disclosed composition, particularly naloxone composition isprovided to the subject at risk for opioid overdose together with atherapeutically effective amount of an opioid agonist. Thus, the opioidreceptor antagonist, specifically naloxone, is administered at atherapeutically effective amount together with a therapeuticallyeffective amount of the opioid agonist, for example morphine, or other,as listed above. The opioid receptor agonist and the opioid/opiate, canbe administered simultaneously or sequentially. For example, the opioidreceptor agonist and the opioid/opiate can be contained in a drug deviceas disclosed herein, in different compartments, that can be actuated bysame or different mechanism. In some embodiments, methods of treatmentaccording to the present disclosure can comprise intranasallyadministering to a subject in need thereof therapeutically effectiveamounts of a short-acting opioid antagonist, such as naloxone ornaltrexone, and a long-acting opioid antagonist, such as for examplenalmefene.

The presently disclosed compositions, drug devices thereof, methods oftreatment and kits can be used also for treating opioid overdosesymptoms. The opioid receptor antagonist, specifically naloxone,prevents or partially or completely reverses the effects of opioidsrespiratory depression, postoperative opioid respiratory depression,altered level consciousness, miotic pupils, cardiovascular depression,hypoxemia, acute lung injury, aspiration pneumonia, sedation, andhypotension. In some embodiments, the respiratory depression is causedby illicit use of opioids or by an accidental misuse of opioids duringmedical opioid therapy. Also, the opioid receptor antagonistcompositions of the present invention, specifically naloxonecompositions as defines herein, can reverse adverse effects variousdrugs that are agonist-antagonists of opioid receptors, such aspentazocine, tramadol, buprenorphine and others. In some embodiments thepatient is not breathing.

With specific regard to naloxone and its pharmaceutically acceptablesalts, an overdose of naloxone has not been reported in humans,notwithstanding some side effects, such as Although naloxone may havesome side effects such as increased blood pressure and cardiac arrest,as well as some others. Therefore, the presently disclosed compositions,dose devices thereof and methods thereof, can be used in preventingcomplications from severe opioid withdrawal. The methods compriseintranasal administration of a dose of the naloxone composition of thepresent disclosure.

Naloxone powder compositions according to the present disclosure can beinitially use by single dose administration, as described herein,followed by monitoring the treated subject's relevant medical indices,such as blood pressure, breathing, etc. If the desired degree ofcounteraction and improvement in respiratory functions is not obtained,administration may be repeated at 2 to 3 minute intervals. If noresponse is observed after administration of about 8-10 mg of naloxone,the diagnosis of narcotic-induced overdose should be assessed.

Accordingly, also provided herein are methods of treating opioidoverdose or a symptom thereof, comprising intranasally administering toa subject in need thereof a therapeutically effective amount of anopioid antagonist, specifically naloxone and pharmaceutically acceptablesalts thereof such as naloxone hydrochloride or hydrate thereof, whereinthe therapeutically effective amount is equivalent, for example to about0.5-15 mg, more specifically about 2-12 mg and any suitable sub-rangethereof of naloxone hydrochloride or a hydrate thereof. One single doseunit specifically starts with 1.5 mg, 2 mg, 4 mg, up to a cumulativedose of 12-15 in multiple administrations.

In all aspects and embodiments of the present disclosure thetherapeutically effective therapeutically effective amount of the opioidantagonist, specifically naloxone and its pharmaceutically acceptablesalts, such as but not limited to naloxone hydrochloride or hydratethereof, is equivalent to about 4 mg, administered intranasally as asingle dose, to about 12 mg or 24 mg of naloxone hydrochloride,optionally administered in several doses. In some embodiments, thetherapeutically effective amount is equivalent to about 3, 4, 5, 6, 7,or 8 to about 9, 10, 11, 12, or 13 mg, respectively, of naloxonehydrochloride. In some embodiments, the opioid antagonist is the onlypharmaceutically active compound in pharmaceutical composition. In someembodiments, the opioid antagonist is naloxone hydrochloride. In someembodiments, the opioid antagonist is anhydrous naloxone hydrochloride.

Methods of treatment with naloxone or other opioid receptor antagonistspowder compositions and formulations according to the present disclosurecan provide for a plasma concentration versus time curve of saidnaloxone hydrochloride in said patient of a T_(max) between about 0.13and about 0.75 hours, for example T_(max) of 0.25 h.

The methods of treatment with naloxone or other opioid receptorantagonists powder compositions and formulations according to thepresent disclosure can provide mean maximum plasma concentration ofnaloxone of about 11.8 ng/mL within 15 minutes of administration.

Further, treatment by intranasal administration of naloxone or otheropioid receptor antagonists powder compositions/formulations accordingto the present disclosure provides for a high share of the naloxoneparticles, respectively other opioid receptor antagonist, comprised inthe powder reaching turbinates and olfactory regions, while only a smallpart of the particles of active agent reaches lower parts of the nasalcavity and less than 15 of the particles reach breathing airways and thelungs. For example, as shown in Example 34, at least 86% reached theturbinates region, more specifically about 35% were the middle part and51% in the upper olfactory area, with less than 10% of the naloxoneparticles found in the nose and less than 1% reaching the lungs. Thisprovides for improved efficacy of the disclosed powder compositions,with the majority of the active agent reaching nasal mucosa and beingabsorbed shortly after administration.

EXAMPLES

The following examples illustrate certain features of the presentinvention but are not intended to limit the scope of the presentinvention. In the examples below, the term “ratio” refers to theweight/weight ratio, except the cases where use of other units isspecifically referred to in the text.

Materials

Sumatriptan succinate (from SMS); lactose monohydrate (from MegglePharma); morphine sulphate and oxycodone hydrochloride (from Noramco);naloxone hydrochloride (from Cilag and Noramco); acetaminophen (fromGreenville Plant); cannabidiol (from THC Pharm); alprazolam (fromCentaur); dopamine hydrochloride and insulin (from Sigma-Aldrich);pramipexole dihydrochloride (from LGM Pharma); ondansetron hydrochloride(from Teva), ethanol and acetone (from BioLab).

Methods

The spray-drying process was carried out using the Mini Spray DryerB-290 of Büchi Labortechnik AG. A magnetic stirrer (Fried Electric) wasplaced under the receiver (receiving chamber), a magnetic bar ofappropriate size was inserted into the receiver, and then the diluentwas added. The liquid feed containing at least one active agent wasprepared by dissolving at least one active compound in the selectedsolvent or mixture of solvents. Quantification was performed using HPLCand a Dionex HPLC instrument. A FEI Quanta-200 Scanning ElectronMicroscope (SEM) equipped with an Everhart-Thornley Detector was used toobtain the images of the spray-dried powder. The accelerating voltage of20 kV was applied to provide magnification from 250 to 10,000 times. Inaddition, an X-ray Element Analysis Detector (Link ISIS, OxfordInstruments, GB) was used to determine the drug and particle identityand their distribution throughout DPI. Particle size was measured usingthe Malvern Mastersizer 3000 series based on the Light Diffractionmethod.

Oxycodone assay in the compositions was performed using Dionex HPLC-PDAinstrument equipped with Chromeleon software. Column: Agilent, ZORBAXSB-CN 4.6×250 mm, 5μ. Mobile phase: 50 mM potassium dihydrogen phosphatebuffer (pH 3.0): acetonitrile (40:60%, v/v). Flow rate: 1.0 mL/min.Column temperature: 25° C. Injection volume: 10 μL.

Oxycodone bio-assay in rat's plasma and brain was performed using DionexHPLC-PDA instrument equipped with Chromeleon software. Detector: UV at210 nm. RT of oxycodone: about 2.6 min. Diluent: water standard andsample final concentration about 4 μg/mL. Column: Agilent, ZORBAX SB-CN4.6×250 mm, 5μ. Gradient: mobile phase A: 50 mM potassium dihydrogenphosphate buffer (pH 3.0): acetonitrile (45:10%, v/v); mobile phase B:acetonitrile. Flow rate: 1.0 mL/min. Column temperature: 25° C.Injection volume: 50 μL. Detection: UV at 210 nm. PDA 200-400 nm.Calibration curve: from 0.1 μg/mL to 4 μg/mL prepared by spiking withrat plasma. Quantitative limit: 0.05 μg/mL. Internal standard:alprazolam.

Processing Oxycodone HCl in Rat Plasma

100 μl plasma (serum) spiked with IS mixed with 600 μL of acetonitrilefor precipitation protein and centrifuged at 14000 rpm for 10 min.Supernatant was dried under nitrogen and reconstituted with 100 μLpotassium dihydrogen phosphate buffer (pH 3.0).

Processing Oxycodone HCl in Rat Brain

Each individual brain tissue was previously weighted and treated by 0.1Mperchloric acid and homogenized. Then it was spiked with IS and mixedwith 1400 μL of acetonitrile. After centrifugation at 14000 rpm for 10min, the upper layer was centrifuged again. Supernatant was dried undernitrogen at 40° C. and reconstituted with 100 μL potassium dihydrogenphosphate buffer (pH 3.0).

Example 1 Spray-Drying of Sumatriptan Succinate Solution without Lactose

This is the reference example for the comparison purposes only.Sumatriptan succinate (12.0 g) was dissolved in 100 ml of deionized (DI)water under stirring at 300 rpm. The resultant clear homogeneoussolution was spray-dried using a Büchi Mini Spray-Dryer with inlet airtemperature of 105° C. and outlet temperature of 62° C., therebyobtaining the dry powder. SEM image (see FIG. 1) showed that theobtained powder was highly aggregated. Large aggregates up to 500microns (μm) are clearly seen on the image.

Example 2 Modification of the Commercial Büchi Labortechnik AGSpray-Dryer

FIG. 2 schematically shows a modified spray dryer of the embodiments. AMini Spray-Dryer B-290 of Büchi Labortechnik AG was modified by:

-   1. Addition of a magnetic bar into the glass receiver and placing a    magnetic stirrer under the continuously rotating glass receiver of    the spray-dryer.-   2. Selection of a suitable two-fluids spraying nozzle for spraying    the solution containing only an active agent (without diluent) into    fine droplets suitable for the preparation of 10-30 μm dry powder    particles of the active agent. One of the fluids is the clear and    homogeneous solution of the active agent, and the second fluid is    the drying gas.

Example 3 Sumatriptan Succinate Composition with Lactose Monohydrate

Sumatriptan succinate (2.3 g) was dissolved in a mixture of acetone (12g) and ethanol (12 g) under stirring at 300 rpm. An appropriate sizemagnetic bar was placed in the receiver and lactose monohydrate (2.3 g)was added there. The stirring rate was set at 150 rpm. The clear andhomogeneous solution of the active agent (sumatriptan succinate) wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 60° C. and outlet temperature of 55° C., thereby obtaining the drypowder of the active agent, which was further blended with lactosemonohydrate in-situ in the receiver. Stirring was being maintainedduring the entire process. The actual weight of sumatriptan as an activeagent in the obtained sumatriptan/lactose composition was 15.4%. Thecomposition was then mixed with an additional amount of lactose in orderto reach the required 10% active agent (sumatriptan) concentration.

Example 4 SEM Imaging of the Sumatriptan Succinate Composition

High resolution SEM imaging coupled with an X-ray Element AnalysisDetector provides the unique opportunity to identify each individualparticle of a formulation by its chemical content. Using this technique,the particles of sumatriptan succinate containing sulphur (S) atoms canbe differentiated from lactose particles containing carbon (C) andoxygen (O) atoms (without sulphur). FIGS. 3 and 4 show the smallspherical API particles having a narrow size distribution ranging from 5μm to 20 μm, which are dispersed between large lactose polyhedronparticles of ranging from 50 μm to 200 μm. FIG. 3 shows thehigh-resolution image with the 100-μm bar and the elemental analysis ofthe particles. FIG. 4 shows the high-resolution image with the 50 μmbar.

Example 5 Particle Size Analysis of the Sumatriptan SuccinateComposition

The sumatriptan succinate composition prepared in Example 3 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument (see FIGS. 5 and 6). The following particle sizedistribution was obtained for the sumatriptan succinate composition (seeFIG. 5): D(10)=7 μm, D(50)=79 μm and D(90)=179 μm. Two populations ofthe particles are clearly seen in the Figures. The 5-25 μm particles aresumatriptan succinate and the 50-200 μm particles are lactosemonohydrate. The amount of the particles having the size less than 5 μmis about 1%. The particle size distribution of sumatriptan succinatealone was estimated in the range of 0-40 μm (see FIG. 6), and thefollowing results were obtained: D(10)=5.2 μm, D(50)=11.2 μm, D(90)=20.1μm and D(99)=27.1 μm.

Example 6 Acetaminophen (Paracetamol) Composition with LactoseMonohydrate

Acetaminophen (paracetamol) (2.3 g) was dissolved in 65 g ethanol understirring at 300 rpm. An appropriate size magnetic bar was placed in thereceiver and lactose monohydrate (2.3 g) was added there. The stirringrate was set at 150 rpm. The clear and homogeneous solution of the drugwas spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 105° C. and outlet temperature of 56° C., therebyobtaining the dry powder of paracetamol, which was further blendedin-situ with lactose monohydrate. Stirring was being maintained duringthe entire process. Concentration of paracetamol in the composition wasfound to be 23% w/w.

Example 7 SEM Imaging of the Paracetamol Composition

The SEM images (not shown here) show that the small spherical particlesof paracetamol having a narrow size distribution of 2-30 μm aredispersed between the large polyhedron particles of lactose ranging from50 μm to 200 μm.

Example 8 Particle Size Analysis of the Paracetamol Composition

The paracetamol composition prepared in Example 6 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained: D(10)=11.6 μm,D(50)=95.4 μm and D(90)=155 μm. Two separate populations of theparticles were clearly seen. The 2-30 μm particles are paracetamol andthe 50-200 μm particles are lactose monohydrate. The percentage of theparticles having the size less than 5 μm was about 7% w/w.

Example 9 Morphine Sulphate Composition with Lactose Monohydrate

Morphine sulphate (2.3 g) was dissolved in a mixture of 18.9 g ethanoland 13.9 g water under stirring at 300 rpm. An appropriate size magneticbar was placed in the receiver and lactose monohydrate (2.3 g) was addedthere. The stirring rate was set at 150 rpm. The clear and homogeneoussolution of the active agent was spray-dried using the Büchi MiniSpray-Dryer with inlet air temperature of 110° C. and outlet temperatureof 86° C., thereby obtaining the dry powder of morphine sulphate, whichwas further blended in-situ with lactose monohydrate in the receiver.Stirring was being maintained during the entire process. Concentrationof morphine sulphate in the composition was about 32% w/w andconcentration of morphine base was about 28% w/w.

Example 10 Particle Size Analysis of the Morphine Sulphate Composition

The morphine sulphate composition prepared in Example 9 was subjected tothe particle size analysis using the Malvern Laser Diffractioninstrument. The following particle size distribution was obtained:D(10)=7.1 μm, D(50)=70.7 μm and D(90)=156 μm. The amount of theparticles having the size less than 5 μm was about 6.6% w/w.

Example 11 Alprazolam Composition with Lactose Monohydrate

Alprazolam (2.3 g) was dissolved in 32.5 g of ethanol under stirring at300 rpm. An appropriate size magnetic bar was placed in the receiver andlactose monohydrate (2.3 g) was added there. The stirring rate was setat 150 rpm. The obtained clear and homogeneous solution of the drug wasthen spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 110° C. and outlet temperature of 86° C., therebyobtaining the dry powder of alprazolam, which was further blendedin-situ with lactose monohydrate in the receiver. Stirring was beingmaintained during the entire process. Concentration of alprazolam in thecomposition was about 33% w/w.

Example 12 Particle Size Analysis of the Alprazolam Composition

The alprazolam—composition prepared in Example 11 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained: D(10)=11.7 μm,D(50)=88.0 μm and D(90)=187 μm. The amount of the particles having thesize less than 5 μm was about 0.6% w/w.

Example 13 SEM Imaging of the Alprazolam Composition

FIG. 7 shows the small polyhedron particles of alprazolam having thenarrow size distribution of 5-40 μm, which are dispersed between thelarge polyhedron particles of lactose ranging from 50 μm to 200 μm. FIG.8a shows an X-ray analysis of the obtained alprazolam polyhedronparticles, where the large particles containing C and O atoms only mustbe lactose, and the small particles additionally containing Cl atomsmust be alprazolam.

Example 14 Oxycodone Hydrochloride Composition with Lactose Monohydrate

Oxycodone hydrochloride (2.3 g) was dissolved in 9.9 g of ethanol understirring at 300 rpm. An appropriate size magnetic bar was placed in thereceiver and lactose monohydrate (2.3 g) was added there. The stirringrate was set at 150 rpm. The clear and homogeneous solution of the drugwas spray-dried using the Büchi Mini Spray-Dryer with inlet airtemperature of 90° C. and outlet temperature of 56° C., therebyobtaining the dry powder of the active agent, which was further blendedin-situ with lactose monohydrate in the receiver. Stirring in thereceiver was being maintained during the entire process. Concentrationof oxycodone hydrochloride in the composition was about 41% w/w andconcentration of oxycodone base was about 37% w/w.

Example 15 SEM Imaging of the Oxycodone Hydrochloride Composition

FIG. 9 shows the small spherical particles of oxycodone hydrochloridehaving the narrow size distribution of 3-30 μm, which are dispersedbetween the large polyhedron particles of lactose ranging from 50 μm to200 μm.

Example 16 Particle Size Analysis of the Oxycodone HydrochlorideComposition

The oxycodone hydrochloride composition prepared in Example 14 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument (see FIG. 10). The following particle sizedistribution was obtained: D(10)=7.7 μm, D(50)=64.4 μm and D(90)=141 μm.The amount of the particles having the size less than 5 μm was about 3%w/w.

Example 17 Dopamine Hydrochloride Composition with Lactose Monohydrate

Dopamine hydrochloride (2.3 g) was dissolved in a mixture of 7.0 gethanol, 7.0 g acetone and 9.0 g water under stirring at 300 rpm. Anappropriate size magnetic bar was placed in the receiver and lactosemonohydrate (2.3 g) was added there. The stirring rate was set at 150rpm. The obtained clear and homogeneous solution of the active agent wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 95° C. and outlet temperature of 65° C., thereby obtaining the drypowder of dopamine hydrochloride, which was further blended in-situ withlactose monohydrate in the receiver. Stirring in the receiver was beingmaintained during the entire process. Concentration of dopaminehydrochloride in the composition was about 37% w/w and concentration ofdopamine base was about 26% w/w.

Example 18 Particle Size Analysis of the Dopamine HydrochlorideComposition

The dopamine hydrochloride composition prepared in Example 17 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument. The following particle size distribution wasobtained: D(10)=8.0 μm, D(50)=74.9 μm and D(90)=147 μm. The amount ofthe particles having the size less than 5 μm was about 3.5% w/w.

Example 19 Insulin Composition with Lactose Monohydrate

5 ml of insulin saline (sodium chloride) solution containing 500 IU ofinsulin was mixed with 7 ml of water under stirring at 300 rpm. Anappropriate size magnetic bar was placed in the receiver and lactosemonohydrate (2.3 g) was added there. The stirring rate was set at 150rpm. The obtained clear and homogeneous solution of insulin wasspray-dried using the Büchi Mini Spray-Dryer with inlet air temperatureof 90° C. and outlet temperature of 56° C., thereby obtaining theinsulin dry powder, which was further blended in-situ with lactosemonohydrate in the receiver. Stirring in the receiver was beingmaintained during the entire process.

Example 20 SEM Imaging of the Insulin Composition

FIG. 11 shows the small spherical particles of insulin-sodium chloridehaving the size of 5-7 μm laid on the surface of the large lactosepolyhedron particles having the size above 100 μm. The elementalanalysis shown on the FIG. 12 confirms that the particles include sodiumchloride and sulphur, which is a clear indication that these particlesare insulin.

Example 21 Particle Size Analysis of the Insulin Composition

The insulin composition prepared in Example 19 was subjected to theparticle size analysis using the Malvern Laser Diffraction instrument.The following particle size distribution was obtained (see FIG. 13):D(10)=57.4 μm, D(50)=97.3 μm and D(90)=151 μm. The amount of theparticles having the size less than 5 μm was about 0.3% w/w.

Example 22 Intranasal Drug Delivery

Aptar Unit-Dose Powder disposable devices were filled with thesumatriptan succinate composition prepared in Example 1. These deviceswere assembled according to the company guideline. Each device contained10 mg of powder including 1 mg of sumatriptan succinate (100 mg/g as alabeled claim). Ten devices were packed, activated, and the powderdelivered upon actuation of each device was collected and weighed. Theweights (mg) of the delivered powder dose from the ten devices are shownin Table 1 below. Uniformity of the delivered dose (mg/g) from each ofthe ten devices, measured with an HPLC instrument according to thecompany protocol, is also shown in Table 1. In addition, Table 1contains the data from the two devices that were stored for 6 months(“6M” in the table) at 40° C. and 75 RH.

TABLE 1 Delivered dose and uniformity of the delivered dose Sampleweight, Sumatriptan base content, Sample name mg mg/g Composition 1-110.04 103.40 Composition 1-2 10.05 93.51 Composition 1-3 10.07 108.63Composition 1-4 9.94 103.28 Composition 1-5 10.07 91.54 Composition 1-610.05 104.63 Composition 1-7 10.04 99.15 Composition 1-8 10.06 122.88Composition 1-9 10.03 109.75 Composition 1-10 10.00 106.86 AVG 10.03104.06 RSD, % 0.4 8.5 Composition 1-11 (6 M) 9.79 97.42 Composition 1-12(6 M) 9.82 104.95 AVG 9.8 101.2 RSD, % 0.3 7.4

Example 23 Plume Geometry and Spray Pattern

Evaluation of the Plume Geometry and Spray Pattern of the compositionsactuated from the Aptar Unit-Dose Powder (UDP) disposable devices wasconducted using FDA's CMC Guidance (9). Three replicates of eachcomposition either fresh prepared or stored were tested for: Plume angle(°); Plume width at 6 cm; Plume length (cm) and duration time (ms).Results from two spray-patterns (3 and 6 cm) were recorded providingdetails on diameter min (cm), diameter max (cm), area and ovality ratio.An appropriate high-resolution visualisation technique was used.

Example 24 PK Evaluation Following Single Intranasal or Oral DoseAdministration of Oxycodone in Rats

The objective of this study was to determine the pharmacokinetic profileof oxycodone following single administration of oral solution ofoxycodone hydrochloride in PBS buffer and intranasal (IN) powder ofoxycodone composition of invention described in the Example 14. Thedosing was done at 10 mg/kg (2 mg per rat) by oral gavage or by modifiedintranasal Aptar device to 12 SD male rats for each rout ofadministration.

Study variables and end points were measured as following:

-   -   1) Morbidity and Mortality—daily.    -   2) Body weight—was measured during acclimation and before Test        Item administrations.    -   3) Clinical sign observation—animals were observed for toxic        signs after dosing.    -   4) Blood withdrawal—blood samples were collected at baseline (24        hours before dosing), 5, 15, 40, 60, 90, 120, 240 and 420        minutes after administration (three rats per bleeding time        points for each Rout of administration).    -   5) Brains were removed after bleeding at time points: 15, 60,        120 and 420 minutes (three rats at each time point for each Rout        of administration)

T_(max), C_(max) and AUC_(t) (area under the concentration-time curvefrom zero up to a definite time t, the parameter that is used as anindex of the drug exposure of the body, when referred to the plasma druglevels, and is closely dependent on the drug amount that enter into thesystemic circulation).

The brain PK parameters were measured in the similar manner and reportedas drug concentration in the ml of homogenized brain tissues. Thesesamples were analysed for oxycodone content by a HPLC-UV method. Theobtained plasma pharmacokinetic parameters of the oral and theintranasal products are shown in Table 2 and FIG. 14.

TABLE 2 Oxycodone pharmacokinetic parameters in rat's plasma C_(max IN)/AUC_(IN)/ Oxycodone AUC₀₋₄₂₀ T_(max) C_(max) C_(max ORAL) AUC_(ORAL)Product (μg * min/ml) (min) (μg/ml) (%) (%) Intranasal powder 4.23 51.88 2.98 1.49 Oral gavage 2.83 60 0.63

As can be seen from the Table 2 and FIG. 14, the C_(max) value is almost3 folds higher, while the AUS value is increased at 1.5 folds uponintranasal administration. The comparative value of T_(max) of 5 minversus 60 min demonstrates the extremely fast onset of action followingintranasal administration of oxycodone. The very fast nasal transmucosalabsorption is manifested by the immediate increase in plasma oxycodoneconcentration, since it is observed following the administering of onlythe intranasal powder. The initial increase is later followed by thesecond peak of 60 min, exhibiting the gastrointestinal absorption, whichis seen both in the intranasal and oral oxycodone formulations.

As the intranasal formulation has been reported to have a more rapidonset of effect (10, 11), which is attributed to the rapid increase inblood levels, the present results suggest that oxycodone intranasalpowder also has a fast pain relief onset of action.

The obtained brain pharmacokinetic parameters of the oral and theintranasal products are shown in Table 3 and FIG. 15.

TABLE 3 Oxycodone pharmacokinetic parameters in rat's brains C_(max IN)/AUC_(IN)/ Oxycodone AUC₀₋₄₂₀ T_(max) C_(max) C_(max ORAL) AUC_(ORAL)Product (μg * min/ml) (min) (μg/ml) (%) (%) Intranasal powder 29.03 4206.63 12.05 11.52 Oral gavage 2.52 120 0.55

As can be seen from the Table 3 and FIG. 15, the C_(max) value is 12folds higher, while the AUS value is increased 11.5 times uponintranasal administration. The T_(max) value of 420 min versus 120 mindemonstrates the sustained action of oxycodone following intranasaladministration. However, the concentrations of the drug after 15 minwere found to be 2.94 μg/ml and 0.23 μg/ml for intranasal and oralroute, respectively. This is the clear evidence that the immediate andhuge increase of oxycodone concentration in brain is a result of thedirect drug delivery to the brain via intranasal route exclusively. Theoxycodone peak in brain of 120 min following the gastrointestinalabsorption is typical for oral oxycodone formulations.

The rapid onset and prolonged action of oxycodone demonstrated in thepresent application is a significant breakthrough in the post-surgerypain management of patients. Both oral and intranasal formulations werewell tolerated. No toxic signals or any abnormal effects were observed.

Intranasal Naloxone Formulations

Materials

Naloxone hydrochloride (Noramco); lactose monohydrate (Meggle Pharma);ethanol (BioLab).

Methods

The spray-drying process was carried out using the Mini Spray DryerB-290 of Büchi Labortechnik AG. A magnetic stirrer (Fried Electric) wasplaced under the receiver (receiving chamber), a magnetic bar ofappropriate size was inserted into the receiver, and then the diluentwas added. The liquid feed containing at least one active agent wasprepared by dissolving at least one active compound in the selectedsolvent or mixture of solvents. Quantification was performed using HPLCand a Dionex HPLC instrument. A FEI Quanta-200 Scanning ElectronMicroscope (SEM) equipped with an Everhart-Thornley Detector was used toobtain the images of the spray-dried powder. The accelerating voltage of20 kV was applied to provide magnification from 250 to 10,000 times. Inaddition, an X-ray Element Analysis Detector (Link ISIS, OxfordInstruments, England) was used to determine the drug and particleidentity and their distribution throughout DPI. Particle size wasmeasured using the Malvern Mastersizer 3000 series based on the LightDiffraction method.

Naloxone assay in the compositions was determined using Dionex HPLC-PDAinstrument equipped with Chromeleon software; Column & packing:LiChroCart®125-4, Li Chrospher®60 RP-select B, 5μ, Part. No.1.50213.0001.

Mobile Phase: A: Acetonitrile: Tetrahydrofuran: Solution A(20:40:940v/v/v)

-   -   B: Acetonitrile: Tetrahydrofuran: Solution A(170:40:790 v/v/v)

Gradient Program:

Time Mobile Phase A Mobile Phase B (min) (%) (%) 0 100 0 40 0 100 50 0100 50.5 100 0 60 100 0

-   Flow rate: 1.5 ml/min-   Injection volume: 20 μL-   Detector: UV, 230 nm-   Column temperature: 40° C.-   Auto sampler temperature: ambient-   Run time: 60 min-   Diluent: 0.1M Hydrochloric acid-   RT of Naloxone peak: about 11 min

Example 25 Modification of the Commercial Büchi Labortechnik AGSpray-Dryer

FIG. 2 schematically shows a modified spray dryer of the embodiments. AMini Spray-Dryer B-290 of Büchi Labortechnik AG was modified by:

-   1. Addition of a magnetic bar into the glass receiver and placing a    magnetic stirrer under the continuously rotating glass receiver of    the spray-dryer.-   2. Selection of a suitable two-fluids spraying nozzle for spraying    the solution containing only an active agent (without diluent) into    fine droplets suitable for the preparation of 10-30 μm dry powder    particles of the active agent. One of the fluids is the clear and    homogeneous solution of the active agent, and the second fluid is    the drying gas.

Example 26 Naloxone Hydrochloride Composition with Lactose Monohydrate

Naloxone hydrochloride (3.0 g) was dissolved for 20 min in 24 g ofethanol-water mixture (50:50) under stirring at 300 rpm. An appropriatesize magnetic bar was placed in the receiver and lactose monohydrate(3.0 g) was added there. The stirring rate was set at 150 rpm. Theobtained clear and homogeneous solution of the drug was spray-driedusing the Büchi Mini Spray-Dryer with inlet air temperature of 115° C.and outlet temperature of 90° C., thereby obtaining the dry powder ofnaloxone hydrochloride, which was further blended in-situ with lactosemonohydrate in the receiver. The stirring was being maintained in thereceiver during the entire process. The loading of naloxonehydrochloride into the composition was about 26% w/w. The obtainedcomposition was then mixed with an additional amount of lactose in orderto reach the 20% API loading.

Example 27 SEM Imaging of the Naloxone Hydrochloride Composition

The SEM images (FIG. 16) show that the small spherical particles ofnaloxone hydrochloride having the narrow size distribution of 5-30 μmare dispersed between large shapeless particles of lactose rangingbetween 40 μm to 240 μm.

Example 28 Particle Size Analysis of the Naloxone HydrochlorideComposition

The naloxone hydrochloride composition prepared in Example 26 wassubjected to the particle size analysis using the Malvern LaserDiffraction instrument. The following particle size distribution wasobtained: D (10)=10.5 μm, D (50)=77.7 μm and D (90)=144 μm. The amountof the obtained particles having the size less than 10 μm was about 9.5%v/v. 5 μm was about 4.9% v/v.

Conclusions:

Particle Size Distribution of Naloxone Microspheres Powder Bulk DrugProduct Specification and Safety Requirements

Example 29 Naloxone HCl Drug-Device Combination Product Preparation

Aptar Unit-Dose Powder disposable devices were filled with the naloxoneHCl composition prepared in Example 26. These devices were assembledaccording to the company guideline. Each device contained 20 mg ofpowder including 4 mg of naloxone hydrochloride (200 mg/g as a labeledclaim).

Example 30 Naloxone HCl Drug-Device Combination Product Net Fill Weightand Delivered Dose Uniformity Tests

Ten devices were packed, activated, and the powder delivered uponactuation of each device (shot weight) was collected and weighed. Theweights (mg) of the delivered powder dose from the ten devices are shownin Table 4 below. Uniformity of the delivered dose (mg/device and %)from each of the ten devices, measured with an HPLC instrument accordingto the company protocol, is also shown in Table 4.

TABLE 4 Net fill weight and uniformity of delivered doses Sample Sample(shot) weight, Naloxone content, Naloxone content, name mg mg/device%/device Device 1 19.04 3.77 99.05 Device 2 19.42 3.84 98.76 Device 319.05 3.77 98.85 Device 4 19.26 3.76 97.74 Device 5 19.96 3.89 97.39Device 6 19.94 3.90 97.75 Device 7 20.16 3.74 92.85 Device 8 19.34 3.6694.61 Device 9 18.82 3.65 97.10 Device 10 20.07 3.82 95.10 AVG 19.513.78 96.92 RSD, % 2.49 2.20 2.13Conclusions:

-   i. Net fill weight of Naloxone Intranasal Product comply Combination    (Drug-Device) Product Specification and USP <755> requirements-   ii. Delivered Dose Uniformity (10 units) of Naloxone Intranasal    Product comply Combination (Drug-Device) Product Specification and    USP <601> requirements

Example 31 Stability Data of Naloxone Drug-Device Combination Product inAccelerating Aging Conditions

The naloxone hydrochloride combination products prepared in Example 29was subjected to accelerating aging conditions at 40° C.±2° C./75% RH±5%RH. The six months stability data is presented in Table 5.

TABLE 5 Stability data Tests and Specifications Testing Impurities/interval, Degradation month Appearance Assay (HPLC) Product WaterContent Specifications Disposable plastic 4.0 ± 0.4 mg A. ≤0.5% NMT 7.0%device, white color, in device B. ≤0.5% no visible damages (90.0-110.0%)C. ≤0.5% F. ≤0.5% E. ≤0.5% Unspecified impurities: ≤0.5% for each TotalImpurities: ≤4.0% Initial Disposable plastic Assay of Naloxone A. ≤BRL ¹6.2% device, white color, hydrochloride B. ≤BRL no visible damages 4.1mg in device C. ≤BRL (103.4%) F. ≤BRL Assay of Naloxone E. ≤BRL 3.8 mgin device Unspecified (94.3%) impurities: ND² Total Impurities: ≤BRL 6Disposable plastic Assay of Naloxone A. 0.1% 1.7% device, white color,hydrochloride B. ≤BRL no visible damages 4.1 mg in device C. 0.2%(103.4%) F. ≤BRL Assay of Naloxone E. ≤BRL 3.8 mg in device D. ≤BRL(94.3%) Unspecified impurities: Imp (RRT1.35) 0.3% Imp (RRT1.9) 0.2%Total Impurities: 0.8% ¹ below reporting limit (0.05%) ²Not Detected

Conclusions: Powdered naloxone formulation according to the presentinvention showed good stability after 6 months at 40° C. and 75% RelatedHumidity RH. It contained 0.8% of the total impurities and similar assayof API. All results meet drug device combination products stabilityspecifications.

Example 32 Structural Characterisation of Naloxone Microspheres Powder

Phase analysis of two naloxone samples was performed by the X-ray powderdiffraction (XRPD) method. The data were collected on a PanalyticalEmpyrean powder diffractometer (Cu Kα radiation, λ=1.54178 Å) equippedwith an X'Celerator linear detector and operated at V=40 kV, I=30 mA.Scans were run in a 2 q range of 3-38° with step equal to ˜0.0167°, scanspeed ˜0.042°/sec. Peak lists were automatically generated using Match!2 p-XRD analysis software.

XRD pattern images of raw naloxone HCl, lactose monohydrate andmicrospheres mixed with lactose monohydrate batch PNLX070729 of thepresent invention are shown in FIG. 18.

As can be seen from FIG. 18, no naloxone HCl peaks are observed in thepattern of naloxone microspheres. The determined peaks belong to lactosemonohydrate, only suggesting that naloxone HCl has an amorphousstructure.

Remarkably, this amorphous structure was shown to be stable for 6months, as shown in FIG. 19. The bottom pattern belongs to the initialproduct while the upper curve reflects the structure after six months.Both patterns are similar.

Thus not only is naloxone stable for at least 6 months, it also retainsan amorphous structure.

Example 33 Comparative Pharmacokinetic Study Between Microspheres NasalPowder 4 mg for and NARCAN® Nasal Spray 4 mg

Study NP-001 was a Phase 1, open-label, single-dose, randomized2-period, 2-treatment, 2-sequence, crossover study. The primaryobjective of this study was to compare the bioavailability (BA) ofnaloxone between FMXIN001 naloxone formulation according to the presentinvention (Microspheres Nasal Powder 4 mg) and NARCAN® (Nasal Spray 4mg) after administration of a single dose in healthy subjects underfasted conditions. The secondary objective of this study was to evaluatethe safety and tolerability of the study treatments.

PK blood samples were collected prior to dosing (0-hour) and at 0.017,0.033, 0.05, 0.067, 0.1, 0.133, 0.167, 0.25, 0.333, 0.417, 0.5, 0.75, 1,2, 3, 4, 6, and 8 hours after drug administration, for a total of 19samples in each period. The 2 study periods were separated by a washoutof 4 days, corresponding to more than 5 times the expected half-life(t_(1/2)) of naloxone to prevent any possible carry-over effect. The PKparameters maximum plasma concentration (C_(max)), area under the drugconcentration versus time curve from time 0 to the time of lastmeasurable analyte concentration (AUC_(t)), area under the drugconcentration versus curve from time 0 to infinity (AUC_(inf)), areaunder the drug concentration versus time curve from time 0 to 4 minutes(AUC_(0-4 min)), area under the drug concentration versus time curvefrom time 0 to 10 minutes (AUC_(0-10 min)), area under the drugconcentration versus time curve from time 10 to 30 minutes(AUC_(10-30 min)), time to maximum plasma concentration (T_(max)),apparent first-order elimination rate constant (K_(el)), and eliminationhalf-life (t_(1/2)) were estimated using a noncompartmental approach fortotal naloxone and unconjugated naloxone (naloxone is metabolized in theliver, primarily by glucuronide conjugation with naloxone-3-glucuronideas the major metabolite).

Study Results

Subject Disposition

Study NP-001 included a total of 14 healthy subjects (6 males and 8females) with a mean age of 43 years (range, 26-58 years). All 14subjects received both treatments (FMXIN001 Microspheres Nasal Powder 4mg and NARCAN® Nasal Spray 4 mg) and completed the study.

Comparative Bioavailability and Bioequivalence

For total naloxone, the total systemic exposure, as measured by AUC_(t)and AUC_(inf), were relatively similar (AUC_(t) ratio=104.31%; AUC_(inf)ratio=102.65%) for FMXIN001 Microspheres Nasal Powder 4 mg compared toNARCAN® Nasal Spray 4 mg. The peak systemic exposure, as measured byC_(max), was approximately 1.1-fold greater for FMXIN001 MicrospheresNasal Powder 4 mg compared to NARCAN® Nasal Spray 4 mg.

Partial exposure as measured by AUC_(0-4 min), AUC_(0-10 min), andAUC_(10-30 min), was approximately 7-fold, 4-fold, and 1.5-fold greater,respectively, for FMXIN001 Microspheres Nasal Powder 4 mg compared toNARCAN® Nasal Spray 4 mg.

The median T_(max) occurred approximately 30 minutes earlier forFMXIN001 Microspheres Nasal Powder 4 mg as compared to NARCAN® NasalSpray 4 mg. The results of the nonparametric analysis show that therewas no statistically significant difference in T_(max) (p=0.2080)between treatments. A significant treatment effect was detected by ANOVAin the analysis of AUC_(0-4 min) (p<0.0001), AUC_(0-10 min) (p=0.0002),and AUC_(10-30 min) (p=0.0088).

A summary of all mean PK parameters for total naloxone is provided inTable 6 and the concentration-time profile is provided in FIG. 20.

TABLE 6 Mean Pharmacokinetic Parameters for Plasma Total NaloxoneTreatment N = 14 FMXIN001 NARCAN ® Microspheres Nasal Mean Parameters(CV %) Powder 4 mg Spray 4 mg C_(max) (ng/mL) 36.74 (30) 33.83 (44)T_(max) ^(a) (h) 1.0 (0.25-2.05) 1.50 (0.42-2.0) AUC_(t) (ng · h/mL)98.06 (15) 94.52 (19) AUC_(inf) (ng · h/mL) 108.89 (20) 103.61 (21)AUC_(0-4 min) (ng · h/mL) 0.14 (88) 0.02 (111) AUC_(0-10 min) (ng ·h/mL) 1.30 (69) 0.39 (63) AUC_(10-30 min) (ng · h/mL) 7.51 (33) 5.14(53) t_(1/2) (h) 2.53 (58) 2.28 (23) K_(el) (1/h) 0.33 (35) 0.32 (22)AUC_(0-4 min) = area under the drug concentration versus time curve fromtime 0 to 4 minutes; AUC_(0-10 min) = area under the drug concentrationversus time curve from time 0 to 10 minutes; AUC_(10-30 min) = areaunder the drug concentration versus time curve from time 10 to 30minutes; AUC_(inf) = area under the drug concentration versus time curvefrom time 0 to infinity; AUC_(t) = area under the drug concentrationversus time curve from time 0 to the time of the last measurable analyteconcentration; C_(max) = maximum plasma concentration; CV = coefficientof variation; K_(el) = first order elimination rate constant; t_(1/2) =elimination half-life T_(max) = time to maximum plasma concentration^(a)Median (range) is presented

For unconjugated naloxone, the total systemic exposure, as measured byAUC_(t) and AUC_(inf), was approximately 1.26-fold greater for FMXIN001Microspheres Powder 4 mg compared to NARCAN® Nasal Spray 4 mg. The peaksystemic exposure, as measured by C_(max), was approximately 1.6-foldgreater for FMXIN001 Microspheres Nasal Powder 4 mg compared to NARCAN®Nasal Spray 4 mg.

Partial exposure as measured by AUC_(0-4 min), AUC_(0-10 min), andAUC_(10-30 min), was approximately 7-fold, 4-fold, and 1.6-fold greater,respectively, for FMXIN001 Microspheres Nasal Powder 4 mg compared toNARCAN® Nasal Spray 4 mg.

The median T_(max) occurred approximately 5 minutes earlier for FMXIN001Microspheres Nasal Powder 4 mg as compared to NARCAN® Nasal Spray 4 mg.The results of the nonparametric analysis show that there was nostatistically significant difference in T_(max) (p=0.1387) betweentreatments. A significant treatment effect was detected by ANOVA in theanalysis of AUC_(t) (p=0.0182), AUC_(inf) (p=0.0190), C_(max)(p=0.0001), AUC_(0-4 min) (p<0.0001), AUC_(0-10 min) (p<0.0001), andAUC_(10-30 min) (p=0.0001).

A summary of all mean PK parameters for unconjugated naloxone isprovided in Table 7 and the concentration-time profile is provided inFIG. 21.

TABLE 7 Mean Pharmacokinetic Parameters for Plasma Unconjugated NaloxoneTreatment N = 14 FMXIN001 NARCAN ® Microspheres Nasal Mean Parameters(CV %) Powder 4 mg Spray 4 mg C_(max) (ng/mL) 11.80 (42) 7.06 (32)T_(max) ^(a) (h) 0.25 (0.13-0.75) 0.33 (0.17-0.75) AUC_(t) (ng · h/mL)14.35 (25) 11.63 (33) AUC_(inf) (ng · h/mL) 14.53 (25) 11.81 (33)AUC_(0-4 min) (ng · h/mL) 0.12 (86) 0.02 (100) AUC_(0-10 min) (ng ·h/mL) 0.94 (69) 0.29 (65) AUC_(10-30 min) (ng · h/mL) 3.01 (34) 1.87(40) t_(1/2) (h) 1.29 (14) 1.29 (12) K_(el) (1/h) 0.55 (13) 0.54 (11)AUC_(0-4 min) = area under the drug concentration versus time curve fromtime 0 to 4 minutes; AUC_(0-10 min) = area under the drug concentrationversus time curve from time 0 to 10 minutes; AUC_(10-30 min) = areaunder the drug concentration versus time curve from time 10 to 30minutes; AUC_(inf) = area under the drug concentration versus time curvefrom time 0 to infinity; AUC_(t) = area under the drug concentrationversus time curve from time 0 to the time of the last measurable analyteconcentration; C_(max) = maximum plasma concentration; CV = coefficientof variation; K_(el) = first order elimination rate constant; t_(1/2) =elimination half-life T_(max) = time to maximum plasma concentration^(a)Median (range) is presented

A statistical summary for the least square (LS) means, ratio of means,and confidence intervals (CIs) for FMXIN001 Microspheres Nasal Powder 4mg versus NARCAN® Nasal Spray 4 mg for total naloxone and unconjugatednaloxone are presented in Table 8 and Table 9, respectively.

TABLE 8 LS Geometric Means, Ratio of Means, and 90% CIs for FMXIN001Microspheres Powder 4 mg versus NARCAN ® Nasal Spray 4 mg for TotalNaloxone LS Geometric Mean N = 14 FMXIN001 NARCAN ® Microspheres NasalRatio 90% Parameters Powder 4 mg Spray 4 mg (%) CI C_(max) (ng/mL) 35.2731.61 111.58  91.29-136.39 AUC_(t) 96.97 92.96 104.31  99.39-109.47 (ng· h/mL) AUC_(inf) ^(a) 107.0 104.24 102.65  97.54-108.02 (ng · h/mL)AUC_(0-4 min) 0.07 0.010 696.13 525.43-922.27 (ng · h/mL) AUC_(0-10 min)1.04 0.25 410.95 249.62-676.56 (ng · h/mL) AUC_(10-30 min) 7.14 4.62154.67 120.59-198.38 (ng · h/mL) AUC_(0-4 min) = area under the drugconcentration versus time curve from time 0 to 4 minutes; AUC_(0-10 min)= area under the drug concentration versus time curve from time 0 to 10minutes; AUC_(10-30 min) = area under the drug concentration versus timecurve from time 10 to 30 minutes; AUC_(inf) = area under the drugconcentration versus time curve from time 0 to infinity; AUC_(t) = areaunder the drug concentration versus time curve from time 0 to the timeof the last measurable analyte concentration; CI = confidence interval;C_(max) = maximum plasma concentration; LS = least squares ^(a)N = 13for FMXIN001 Microspheres Powder 4 mg and N = 12 for NARCAN ® NasalSpray due to analytical reasoning

TABLE 9 LS Geometric Means, Ratio of Means, and 90% CIs for FMXIN001Microspheres Powder 4 mg versus NARCAN ® Nasal Spray 4 mg forUnconjugated Naloxone LS Geometric Mean N = 14 FMXIN001 NARCAN ®Microspheres Nasal Ratio 90% Parameters Powder 4 mg Spray 4 mg (%) CIC_(max) (ng/mL) 10.95 6.75 162.29 138.29-190.45 AUC_(t) 13.94 11.04126.32 108.46-147.12 (ng · h/mL) AUC_(inf) 14.11 11.21 125.87108.18-146.46 (ng · h/mL) AUC_(0-4 min) 0.07 0.01 683.48 447.84-1043.1(ng · h/mL) AUC_(0-10 min) 0.74 0.20 373.24 253.04-550.53 (ng · h/mL)AUC_(10-30 min) 2.86 1.74 164.27 138.93-194.24 (ng · h/mL) AUC_(0-4 min)= area under the drug concentration versus time curve from time 0 to 4minutes; AUC_(0-10 min) = area under the drug concentration versus timecurve from time 0 to 10 minutes; AUC_(10-30 min) = area under the drugconcentration versus time curve from time 10 to 30 minutes; AUC_(inf) =area under the drug concentration versus time curve from time 0 toinfinity; AUC_(t) = area under the drug concentration versus time curvefrom time 0 to the time of the last measurable analyte concentration; CI= confidence interval; C_(max) = maximum plasma concentration; LS =least squares

Overall, FMXIN001 Microspheres Nasal Powder 4 mg displayed greater peakand total systemic exposure, with earlier onset of action (supported bygreater partial exposures) for total and unconjugated naloxone whencompared to NARCAN® Nasal Spray 4 mg after a single dose in healthysubjects under fasted conditions.

These results demonstrate that the FMXIN001 Microspheres Nasal Powderdrug delivery system (UDS) results in exposures that are eithercomparable or superior to NARCAN® Nasal Spray.

Safety

The administration of FMXIN001 Microspheres Nasal Powder 4 mg wasgenerally well tolerated by the healthy subjects who participated inthis study.

A total of 9 treatment-emergent adverse events (TEAEs) affecting 4subjects (28.6% of subjects dosed) were reported during administrationof FMXIN001 Microspheres Nasal Powder and NARCAN® Nasal Spray. All TEAEswere considered mild in severity, possibly related to the studytreatment, not related to the study device, and resolved prior to theend-of-study without intervention. The most prevalent TEAE wasbradycardia, with 3 events affecting 2 subjects (14.3%) (Table 7).

No subject discontinued from the study due to a TEAE, and none of theTEAEs required the use of concomitant therapy. No serious adverse events(SAEs) were reported during the conduct of the study and none of the AEshad a significant impact on the safety of the subjects or on theintegrity of the study results.

Overall, the safety profile of FMXIN001 Microspheres Nasal Powder wascomparable to the safety profile of NARCAN® Nasal Spray (Table 10).

TABLE 10 Summary of Adverse Events Incidence by Treatment Group n(%) ofSubjects FMXIN001 NARCAN ® Microspheres Nasal System Organ Class Powder4 mg Spray 4 mg Total Preferred Term N = 14 N = 14 N = 14 Subjects with1 or More 3 (21.4%) 3 (21.4%) 4 (28.6%) TEAEs Subjects with No TEAEs 11(78.6%) 11 (78.6%) 10 (71.4%) Cardiac Disorders 1 (7.1%) 2 (14.3%) 2(14.3%) Bradycardia 1 (7.1%) 2 (14.3%) 2 (14.3%) Investigations 1 (7.1%)2 (14.3%) 2 (14.3%) Electrocardiogram PR 0 (0%) 1 (7.1%) 1 (7.1%)Prolongation Electrocardiogram QT 1 (7.1%) 1 (7.1%) 1 (7.1%)Prolongation Nervous System Disorders 1 (7.1%) 0 (0%) 1 (7.1%) Dizziness1 (7.1%) 0 (0%) 1 (7.1%) Respiratory, Thoracic, 1 (7.1%) 0 (0%) 1 (7.1%)and Mediastinal Disorders Tachypnoea 1 (7.1%) 0 (0%) 1 (7.1%) Skin andSubcutaneous 1 (7.1%) 0 (0%) 1 (7.1%) Tissue Disorders Cold Sweat 1(7.1%) 0 (0%) 1 (7.1%) TEAE = treatment-emergent adverse eventDose Accuracy

To evaluate the dose accuracy of FMXIN001 Microspheres Nasal Powdercompared to NARCAN® Nasal Spray after device actuation, the weight ofeach study drug device was measured and documented within 2 hours beforethe first subject dosing time and after the last subject's drugadministration. The device weight differences for each subjectadministered FMXIN001 Microspheres Nasal Powder and NARCAN® Nasal Sprayare provided in Table 11 and Table 12, respectively.

Overall, the dose accuracy was comparable between FMXIN001 MicrospheresNasal Powder and NARCAN® Nasal Spray. The average dose remaining in eachdevice after actuation of the drug product was 0.018714 g (standarddeviation [SD], 0.001485; relative standard deviation [RSD], 7.933057%)for FMXIN001 Microspheres Nasal Powder compared to 0.104214 g (SD,0.003004; RSD, 2.882761%) for NARCAN® Nasal Spray. The dose accuracy ofFMXIN001 Microspheres Nasal Powder was observed following pilotproduction and manual filling of devices. Automated commercial batchesfilling equipment can provide for uniform accuracy.

TABLE 11 Individual Dose Accuracy of FMXIN001 Microspheres Nasal PowderDevice Weight Device Weight Device Weight Before Dosing After DosingDifference Subject Period (g) (g) (g) 1 2 6.601 6.583 0.018 2 2 6.66.582 0.018 3 1 6.592 6.569 0.023 4 1 6.62 6.599 0.021 5 2 6.612 6.5950.017 6 1 6.608 6.59 0.018 7 1 6.616 6.597 0.019 8 2 6.615 6.597 0.018 91 6.617 6.599 0.018 10 2 6.602 6.584 0.018 11 2 6.615 6.597 0.018 12 16.616 6.597 0.019 13 2 6.602 6.584 0.018 14 1 6.608 6.589 0.019

TABLE 12 Individual Dose Accuracy of NARCAN ® Nasal Spray Device WeightDevice Weight Device Weight Subject Period Before Dosing After DosingDifference 1 1 5.216 5.112 0.104 2 1 5.194 5.089 0.105 3 2 5.192 5.0920.1 4 2 5.209 5.106 0.103 5 1 5.199 5.093 0.106 6 2 5.19 5.085 0.105 7 25.192 5.086 0.106 8 1 5.181 5.07 0.111 9 2 5.208 5.107 0.101 10 1 5.1885.084 0.104 11 1 5.197 5.097 0.1 12 2 5.189 5.081 0.108 13 1 5.173 5.0680.105 14 2 5.211 5.11 0.101Conclusion

Study NP-001 was designed based on the FDA draft guidance NaloxoneHydrochloride (2017) and the Summary Review of Regulatory Action (2015)for NARCAN® Nasal Spray where it was determined that designing anefficacy study to define an effective range of naloxone used in theproposed setting would be difficult to justify as it would requireadministration of opioids to create an overdose, albeit in a controlledsetting. Therefore, given the known safety profile of naloxone, theapproach required by the division was to conduct a relativebioavailability study in healthy subjects that demonstrated the newproduct matched or exceeded the PK parameters of C_(max) and T_(max) fornaloxone by an approved route. It was noted that the first few minuteswere of particular importance, because if the overdose has led to apnea,time is of the essence if the brain is to be spared permanent hypoxicinjury. Therefore, in addition to C_(max) and T_(max), it was necessaryto demonstrate that the naloxone levels were comparable to the approvedroute during the first minutes after dosing.

The dose accuracy data from Study NP-001 supports that patients receivedcomparable doses of both FMXIN001 Microspheres Nasal Powder and NARCAN®Nasal Spray demonstrated that FMXIN001 Microspheres Nasal Powder 4 mgdisplayed greater peak and total systemic exposure, with earlier onsetof action (supported by greater partial exposures) for total andunconjugated naloxone when compared to NARCAN® Nasal Spray 4 mg after asingle dose in healthy subjects under fasted conditions, supporting thepotential benefit of overdose subjects to absorb naloxone more quicklyin those first few critical minutes. Further, no SAEs were reported andno TEAEs led to discontinuation by any subject. FMXIN001 MicrospheresNasal Powder demonstrated a similar safety profile to NARCAN® NasalSpray 4 mg.

Example 34 Nasal Cast Deposition Using Unitdose Device with aMicrospheres Naloxone Powder

Device: Unitdose powder device was provided by Aptar as described above.The Caucasian male nasal cast (was developed by Aptar in collaborationwith Nasus Pharma). Naloxone HCl microspheres blend with lactose wasprepared at Formulex for Nasus Pharma, Noramco API was used.

The deposition of the Naloxone in the Nasal Cast was studied byapplication of the Unitdose device loaded with 20 mg of Naloxonehydrochloride powder formulation. The assay of Naloxone HCl was 20.6%,i.e. about 4.1 mg of drug was applied by actuation.

Tests were performed in Aptar laboratory on a Caucasian male nasal castusing a specific “Jig” which assures specific:

-   -   Holding angle: 45°    -   Angle from central wall: 4°    -   Insertion depth: 15 mm

Three trials were performed. Two doses were delivered each time, onedose in each nostril. Samples were collected from the nasal cast byrinsing each region of interest with water. The content of Naloxone wasanalyzed spectrophotometrically at 229 nm.

Study Results:

The mass of naloxone recovered in all regions of interest are summarizedin Table 13.

TABLE 10 Mass of Naloxone recovered in each region of interest Naloxone(in μg) Trial 1 Trial 2 Trial 3 Nose and Nasal valve 573 318 443 Floor125 256 119 Turbinates (Middle) 2917 2172 3165 Olfactory Area 3830 40484129 Rhino-Pharynx 383 477 433 Filter/Lungs 47 59 29 Total recovery 78767328 8317 Overall Mean 7840 Overall SD 495

The expected value of naloxone upon 2 doses administration is 8200 μg.The high and reproducible recovery of 95.6% evidences high experimentsquality.

Table 14 and FIG. 22 summarize the percentage deposition of naloxone ineach region of interest.

TABLE 11 % Naloxone in each Region of Interest Overall Overall Naloxone(in μg) Trial 1 Trial 2 Trial 3 mean SD Nose and Nasal valve 7 4 5 6 1Floor 2 3 1 2 1 Turbinates (Middle) 37 30 38 35 5 Olfactory Area 49 5550 51 4 Rhino-Pharynx 5 7 5 6 1 Filter/Lungs 1 1 0 1 0As shown, when the naloxone intranasal powder composition in accordancewith the present disclosure was administered by means of a unitdosedevice for intranasal administration loaded with the composition, a highproportion of the naloxone particle of at least 86% reached theturbinates region, more specifically about 35% were the middle part and51% in the upper olfactory area. Less than 10% of the naloxone particleswere in the nose and less than 1% reached the lungs.

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The invention claimed is:
 1. A pharmaceutical composition in a form ofdry powder for intranasal administration, comprising (1) a first type ofsolid particles and (2) a second type of solid particles, wherein thefirst type particles consist of at least one opioid receptor antagonistas active ingredient, and the second type of solid particles comprise apharmaceutically acceptable disaggregating agent, wherein at least 90%of said first type particles are of a mean particle size of about 10 toabout 30 microns, and less than about 10% of said first type particlesare of a mean particle size equal to or below about 10 microns and saidsecond type particles are of a mean particle size greater than that ofsaid first type particles.
 2. The pharmaceutical composition accordingto claim 1, wherein less than about 5% of said first type particles areof a mean particle size of or below 5 microns.
 3. The pharmaceuticalcomposition of claim 1, wherein said second type particles are of a meansize of about 50 to about 200 microns.
 4. The pharmaceutical compositionof claim 1, wherein said second type particles are of a mean size ofabout 50 to about 150 microns.
 5. The pharmaceutical composition ofclaim 1, wherein said first type particles are of a substantiallyspherical form and said second type particle are of an irregular shape.6. The pharmaceutical composition of claim 1, comprising saiddisaggregating agent as the only excipient for preventing aggregation ofthe solid particles of the active ingredient and preserving theiroriginal size and shape in said composition.
 7. The pharmaceuticalcomposition of claim 1, wherein said at least one opioid receptorantagonist any one of naloxone, naltrexone, almivopan, methylnaltrexone,naloxegon or naldemidine and pharmaceutically acceptable salts thereofand solvates or hydrates thereof, wherein said salt is any of chloride,bromide, oxalate, chloride, tosylates or tosylate.
 8. The pharmaceuticalcomposition of claim 1, wherein said at least one opioid receptorantagonist is naloxone or naloxone hydrochloride, or solvate or hydratethereof.
 9. The pharmaceutical composition of claim 1, wherein saiddisaggregating agent is any one of lactose monohydrate, lactose, alactose functional analogue, or any mixture of at least two thereof. 10.The pharmaceutical composition of claim 1, wherein said disaggregatingis any one of dextrose, sorbitol, mannitol, maltitol and xylitol, acellulose or cellulose derivative, or starch or starch derivative, orany mixture of at least two thereof.
 11. The pharmaceutical compositionof claim 1, wherein the weight ratio between said first type particlesand said second type particles is between about 1:9 to about 9:1. 12.The pharmaceutical composition of claim 11, wherein the weight ratiobetween said first type particles and said second type particles is fromabout 1:9 to about 4:6.
 13. A naloxone pharmaceutical composition in theform of dry powder for intranasal administration, comprising (1) a firsttype of solid particles and (2) a second type of solid particles,wherein the first type particles consist of as active agent naloxone ora pharmaceutically acceptable salt thereof as active agent, and thesecond type of solid particles comprise lactose monohydrate asdisaggregation agent, wherein at least about 90% of said first typeparticles are of a mean particle size of about 10-30 microns and lessthan about 10% of said first type particles are of a mean particle sizeequal to or below about 10 microns and said second type particles are ofa mean particle size greater than that of said first type particles,providing a metered therapeutically effective nominal dose of saidnaloxone or pharmaceutically acceptable salt thereof.
 14. The naloxonepharmaceutical composition of claim 13, wherein the weight ratio betweensaid first type particles and said second type particles is from about1:9 to about 4:6.
 15. The naloxone pharmaceutical composition of claim13, comprising about 20% w/w, about 15% w/w, about 10% w/w, about 8% w/wor about 5% w/w naloxone or said pharmaceutically acceptable saltthereof or solvate or hydrate thereof.
 16. The naloxone pharmaceuticalcomposition of claim 13, wherein said therapeutically nominal dose ofnaloxone is about 4 mg.
 17. A disposable dose unit form for singleintranasal administration to a subject of a pharmaceutical compositionaccording to claim 1, wherein said dose unit is loaded with apredetermined dose of the composition and provides the subject with atherapeutically effective metered dose of said active opioid receptorantagonist.
 18. A disposable dose unit form for single intranasaladministration to a subject of a pharmaceutical composition according toclaim 13, wherein said dose unit is loaded with a predetermined dose ofthe composition and provides the subject with a therapeuticallyeffective metered dose naloxone or said pharmaceutically acceptable saltthereof.
 19. The disposable unit of claim 18, wherein saidtherapeutically effective metered dose naloxone or said pharmaceuticallyacceptable salt thereof is 4 mg per said single administration.
 20. Akit for intranasal administration of naloxone comprising: a. at leastone dose unit for single intranasal administration comprising apharmaceutical composition as defined in claim 17; and b. instructionsfor use.
 21. A method of treating opioid overdose/intoxication and/or asymptom thereof in a patient in need thereof, said method comprisingintranasally administering to said patient a therapeutically effectiveamount of a composition as defined in claim
 1. 22. The method of claim21, wherein said symptom associated with opioid overdose/intoxication isany one of respiratory depression, central nervous system depression,cardiovascular depression, altered level consciousness, miotic pupils,hypoxemia, acute lung injury, aspiration pneumonia, sedation,hypotension, unresponsiveness to stimulus, unconsciousness, stoppedbreathing; erratic or stopped pulse, choking or gurgling sounds, blue orpurple fingernails or lips, slack or limp muscle tone, contractedpupils, and vomiting.
 23. A method of treating opioidoverdose/intoxication and/or a symptom thereof in a patient in needthereof, said method comprising intranasally administering to saidpatient a therapeutically effective amount of a composition as definedin claim
 13. 24. The method of claim 23, wherein a single intranasaladministration provides said patient with a dose unit of 1.5, 2, 3 or 4mg naloxone or said pharmaceutically acceptable salt thereof.
 25. Themethod of claim 23, wherein said symptom associated with opioidoverdose/intoxication is any one of respiratory depression, centralnervous system depression, cardiovascular depression, altered levelconsciousness, miotic pupils, hypoxemia, acute lung injury, aspirationpneumonia, sedation, hypotension, unresponsiveness to stimulus,unconsciousness, stopped breathing, erratic or stopped pulse, choking orgurgling sounds, blue or purple fingernails or lips, slack or limpmuscle tone, contracted pupils, and vomiting.
 26. The method of claim23, wherein said patient is not breathing.
 27. The method of claim 24,wherein administration said dose unit can be repeated at 2 to 3 minuteintervals, up to a cumulative dose of from about 8 mg to about 10 mg andup to about 15 mg of naloxone.
 28. The method of claim 24, the methodfurther comprising administration of an opioid, wherein said opioid isadministered simultaneously with said dose unit of naloxone orseparately.
 29. The method of claim 24, wherein by said dose unitintranasal administration the major part of over 50% of the said firsttype solid particles reach turbinates region in the intranasal cavity,and less than 1% of said first type solid particles reach the lungs ofsaid patient.
 30. The method of claim 24, wherein by said dose unitintranasal administration is at least 85% of the said first type solidparticles reach turbinates region in the intranasal cavity, less thanabout 10% of said first type solid particles reach another region of theintranasal cavity, and less than 1% of said first type solid particlesreach the lungs of said patient.
 31. The pharmaceutical composition ofclaim 11, wherein the weight ratio between said first type particles andsaid second type particles is about 2:8.